807 results
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2. The tissue distribution of NK-9 positive lymphoid cells including NK and AK cells and their precursors.
- Author
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Nieminen P
- Subjects
- Antibodies, Monoclonal, Collodion, Electrophoresis, Polyacrylamide Gel, Histocytochemistry, Humans, Lymph Nodes cytology, Lymphoid Tissue immunology, Palatine Tonsil cytology, Paper, Spleen cytology, Thymus Gland cytology, Tissue Distribution, Antigen-Presenting Cells immunology, Antigens, Surface immunology, Killer Cells, Natural immunology, Lymphoid Tissue cytology
- Abstract
The distribution of NK-9 antigen presenting cells in human lymphoid tissues including spleen, tonsil, lymph node, and thymus was studied. The staining were done on formalin-fixed, histological sections. In peripheral blood NK-9 antigens are expressed on allospecific (CTL) and nonspecific (NK and AK) cytotoxic lymphocytes. In lymphoid tissues, the distribution of NK-9 positive cells was definitely different from "normal" T cell distribution, measured by pan T monoclonal markers. In tonsils and lymph nodes NK-9 positive cells were mainly located in and around germinal centers. However, only a proportion of these areas were NK-9 positive. In spleen NK-9 positive cells were located mainly in periarteriolar lymphocyte sheats and in germinal centers. Thymuses were practically NK-9 negative. These results support the earlier suggestions that cytotoxic cells take part in the immunoregulation in lymphoid tissues.
- Published
- 1986
- Full Text
- View/download PDF
3. Commentary on journal of immunotherapy paper by melenhorst et al
- Author
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Helen E. Heslop
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Pharmacology ,Cancer Research ,Antigen Presentation ,business.industry ,medicine.medical_treatment ,T-Lymphocytes ,Immunology ,Antigen presentation ,MEDLINE ,Antigen-Presenting Cells ,Cytomegalovirus ,Immunotherapy ,Lymphocyte Activation ,Phosphoproteins ,Viral Matrix Proteins ,Text mining ,Lymphocyte activation ,Immunology and Allergy ,Medicine ,Humans ,business - Published
- 2006
4. Virion-surface display of a chimeric immunoglobulin Fc domain facilitating uptake by antigen-presenting cells.
- Author
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Seki S, Parbie PK, Yamamoto H, and Matano T
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- Animals, Mice, Macrophages metabolism, Macrophages immunology, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins metabolism, Recombinant Fusion Proteins immunology, Simian Immunodeficiency Virus immunology, Simian Immunodeficiency Virus genetics, Hemagglutinin Glycoproteins, Influenza Virus immunology, Hemagglutinin Glycoproteins, Influenza Virus genetics, Hemagglutinin Glycoproteins, Influenza Virus metabolism, Cell Line, Leukemia Virus, Murine genetics, Phagocytosis, Humans, Immunoglobulin Fc Fragments genetics, Immunoglobulin Fc Fragments metabolism, Immunoglobulin Fc Fragments immunology, Antigen-Presenting Cells immunology, Antigen-Presenting Cells metabolism, Virion metabolism, Virion genetics, Dendritic Cells immunology, Dendritic Cells metabolism
- Abstract
Antigen-presenting cells (APCs) play an important role in virus infection control by bridging innate and adaptive immune responses. Macrophages and dendritic cells (DCs) possess various surface receptors to recognize/internalize antigens, and antibody binding can enhance pathogen-opsonizing uptake by these APCs via interaction of antibody fragment crystallizable (Fc) domains with Fc receptors, evoking profound pathogen control in certain settings. Here, we examined phagocytosis-enhancing potential of Fc domains directly oriented on a retroviral virion/virus-like particle (VLP) surface. We generated an expression vector coding a murine Fc fragment fused to the transmembrane region (TM) of a retroviral envelope protein, deriving expression of the Fc-TM fusion protein on the transfected cell surface and production of virions incorporating the chimeric Fc upon co-transfection. Incubation of Fc-displaying simian immunodeficiency virus (SIV) with murine J774 macrophages and bone marrow-derived DCs derived Fc receptor-dependent enhanced uptake, being visualized by imaging cytometry. Alternative preparation of a murine leukemia virus (MLV) backbone-based Fc-displaying VLP loading an influenza virus hemagglutinin (HA) antigen resulted in enhanced HA internalization by macrophages, stating antigen compatibility of the design. Results show that the Fc-TM fusion molecule can be displayed on certain viruses/VLPs and may be utilized as a molecular adjuvant to facilitate APC antigen uptake., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
5. Nanobody-liposomes as novel cancer vaccine platform to efficiently stimulate T cell immunity.
- Author
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Bouma RG, Nijen Twilhaar MK, Brink HJ, Affandi AJ, Mesquita BS, Olesek K, van Dommelen JMA, Heukers R, de Haas AM, Kalay H, Ambrosini M, Metselaar JM, van Rooijen A, Storm G, Oliveira S, van Kooyk Y, and den Haan JMM
- Subjects
- Animals, Humans, Mice, Female, Antigens, Neoplasm immunology, Antigens, Neoplasm administration & dosage, Lymphocyte Activation drug effects, Liposomes, Cancer Vaccines administration & dosage, Cancer Vaccines immunology, Single-Domain Antibodies immunology, Single-Domain Antibodies administration & dosage, T-Lymphocytes immunology, Mice, Inbred C57BL, Antigen-Presenting Cells immunology
- Abstract
Cancer vaccines can be utilized in combination with checkpoint inhibitors to optimally stimulate the anti-tumor immune response. Uptake of vaccine antigen by antigen presenting cells (APCs) is a prerequisite for T cell priming, but often relies on non-specific mechanisms. Here, we have developed a novel vaccination strategy consisting of cancer antigen-containing liposomes conjugated with CD169- or DC-SIGN-specific nanobodies (single domain antibodies) to achieve specific uptake by APCs. Our studies demonstrate efficient nanobody liposome uptake by human and murine CD169
+ and DC-SIGN+ APCs in vitro and in vivo when compared to control liposomes or liposomes with natural ligands for CD169 and DC-SIGN. Uptake of CD169 nanobody liposomes resulted in increased T cell activation by human APCs and stimulated naive T cell priming in mouse models. In conclusion, while nanobody liposomes have previously been utilized to direct drugs to tumors, here we show that nanobody liposomes can be applied as vaccination strategy that can be extended to other receptors on APCs in order to elicit a potent immune response against tumor antigens., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)- Published
- 2024
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6. Engineering antigen-presenting cells for immunotherapy of autoimmunity.
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Smith CT, Wang Z, and Lewis JS
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- Humans, Animals, Antigen-Presenting Cells immunology, Autoimmune Diseases immunology, Autoimmune Diseases therapy, Immunotherapy methods, Autoimmunity immunology
- Abstract
Autoimmune diseases are burdensome conditions that affect a significant fraction of the global population. The hallmark of autoimmune disease is a host's immune system being licensed to attack its tissues based on specific antigens. There are no cures for autoimmune diseases. The current clinical standard for treating autoimmune diseases is the administration of immunosuppressants, which weaken the immune system and reduce auto-inflammatory responses. However, people living with autoimmune diseases are subject to toxicity, fail to mount a sufficient immune response to protect against pathogens, and are more likely to develop infections. Therefore, there is a concerted effort to develop more effective means of targeting immunomodulatory therapies to antigen-presenting cells, which are involved in modulating the immune responses to specific antigens. In this review, we highlight approaches that are currently in development to target antigen-presenting cells and improve therapeutic outcomes in autoimmune diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
7. DNA methylation in the promoters of PD-L1, MMP9, ARG1, galectin-9, TIM-3, VISTA and TGF-β genes in HLA-DR– myeloid cells, compared with HLA-DR+ antigen-presenting cells
- Author
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Saleh, Reem, Toor, Salman M., Taha, Rowaida Z., Al-Ali, Dana, Sasidharan Nair, Varun, and Elkord, Eyad
- Subjects
DNA methylation ,immunosuppression ,B7 Antigens ,epigenetics ,Arginase ,MDSC ,Sialic Acid Binding Ig-like Lectin 3 ,Antigen-Presenting Cells ,HLA-DR Antigens ,B7-H1 Antigen ,Epigenesis, Genetic ,Matrix Metalloproteinase 9 ,Genetic Loci ,Transforming Growth Factor beta ,Humans ,Myeloid Cells ,Promoter Regions, Genetic ,Hepatitis A Virus Cellular Receptor 2 ,Research Article ,Research Paper - Abstract
Myeloid cells, including antigen-presenting cells (APCs) and myeloid-derived suppressor cells (MDSCs) play opposing roles to orchestrate innate and adaptive immune responses during physiological and pathological conditions. We investigated the role of DNA methylation in regulating the transcription of inhibitory/suppressive molecules in myeloid suppressive cells (identified as CD33+HLA-DR–) in comparison to APCs. We selected a number of immune checkpoints (ICs), IC ligands, and immunosuppressive molecules that have been implicated in MDSC function, including PD-L1, TIM-3, VISTA, galectin-9, TGF-β, ARG1 and MMP9. We examined their mRNA expression levels, and investigated whether DNA methylation regulates their transcription in sorted myeloid cell subpopulations. We found that mRNA levels of PD-L1, TIM-3, TGF-β, ARG1 and MMP9 in CD33+HLA-DR– cells were higher than APCs. However, VISTA and galectin-9 mRNA levels were relatively similar in both myeloid subpopulations. CpG islands in the promoter regions of TGF-β1, TIM-3 and ARG1 were highly unmethylated in CD33+HLA-DR–cells, compared with APCs, suggesting that DNA methylation is one of the key mechanisms, which regulate their expression. However, we did not find differences in the methylation status of PD-L1 and MMP9 between CD33+HLA-DR– and APCs, suggesting that their transcription could be regulated via other genetic and epigenetic mechanisms. The promoter methylation status of VISTA was relatively similar in both myeloid subpopulations. This study provides novel insights into the epigenetic mechanisms, which control the expression of inhibitory/suppressive molecules in circulating CD33+HLA-DR– cells in a steady-state condition, possibly to maintain immune tolerance and haemostasis.
- Published
- 2020
8. Differential immune responses of C57BL/6 mice to infection by Salmonella enterica serovar Typhimurium strain SL1344, CVCC541 and CMCC50115
- Author
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Hongbing Han, Zhexi Liu, Shao Wei, Bingkun Zhang, Mengyao Wang, Jianwei Huang, Zhengxing Lian, and Guo Yuming
- Subjects
Microbiology (medical) ,Serotype ,mice ,salmonella enterica serovar typhimurium ,T-Lymphocytes ,Immunology ,Antigen-Presenting Cells ,Virulence ,Spleen ,Biology ,Microbiology ,immune response ,lcsh:Infectious and parasitic diseases ,03 medical and health sciences ,Immune system ,Species Specificity ,medicine ,Animals ,lcsh:RC109-216 ,Gene ,030304 developmental biology ,Salmonella Infections, Animal ,0303 health sciences ,Innate immune system ,030306 microbiology ,Genetic Variation ,Salmonella enterica ,biology.organism_classification ,Immunity, Innate ,Mice, Inbred C57BL ,virulence ,Infectious Diseases ,medicine.anatomical_structure ,Mutation ,bacteria ,Female ,Parasitology ,Host adaptation ,Research Paper - Abstract
With a broad range of hosts, Salmonella enterica serovar Typhimurium (S. Typhimurium) is the major cause of gastroenteritis in human beings and systemic disease in susceptible mice strains. However, different S. Typhimurium strains differ in regard to virulence and host adaptation. Here, C57BL/6 mice were infected, respectively, with different S. Typhimurium strains SL1344 (calf), CVCC541 (chicken) and CMCC50115 (mutton) to determine their virulence and host immune responses. It was found that mice were less susceptible to infection by S. Typhimurium CVCC541 and CMCC50115 strains, with lower lethality and decreased bacterial burden in liver and spleen. Besides, S. Typhimurium strains CVCC541 and CMCC50115 enhanced host innate immune responses by increased frequencies of macrophages and neutrophils 3 days after infection. But SL1344 strain evaded immune response by inducing apoptosis of macrophages. Moreover, CVCC541 could elicit adaptive immune responses of host 11 days after infection upon examination of the proliferation and activation of CD4+ T cells. In addition, 125 and 138 unique mutant coding genes, respectively, in S. Typhimurium strains CVCC541 and CMCC50115 and 78 shared mutant coding genes were annotated by genomic alignment to SL1344 genome and the signal pathways involving these genes were further analyzed. The acquired results indicate that different original S. Typhimurium strains show differential virulence and may induce diverse immune responses in the same host infected.
- Published
- 2019
9. Ligand Recognition by the Macrophage Galactose-Type C-Type Lectin: Self or Non-Self?-A Way to Trick the Host's Immune System.
- Author
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Szczykutowicz J
- Subjects
- Male, Humans, Ligands, Macrophages metabolism, Lectins, C-Type metabolism, Galactose, Antigen-Presenting Cells metabolism
- Abstract
The cells and numerous macromolecules of living organisms carry an array of simple and complex carbohydrates on their surface, which may be recognized by many types of proteins, including lectins. Human macrophage galactose-type lectin (MGL, also known as hMGL/CLEC10A/CD301) is a C-type lectin receptor expressed on professional antigen-presenting cells (APCs) specific to glycans containing terminal GalNAc residue, such as Tn antigen or LacdiNAc but also sialylated Tn antigens. Macrophage galactose-type lectin (MGL) exhibits immunosuppressive properties, thus facilitating the maintenance of immune homeostasis. Hence, MGL is exploited by tumors and some pathogens to trick the host immune system and induce an immunosuppressive environment to escape immune control. The aims of this article are to discuss the immunological outcomes of human MGL ligand recognition, provide insights into the molecular aspects of these interactions, and review the MGL ligands discovered so far. Lastly, based on the human fetoembryonic defense system (Hu-FEDS) hypothesis, this paper raises the question as to whether MGL-mediated interactions may be relevant in the development of maternal tolerance toward male gametes and the fetus.
- Published
- 2023
- Full Text
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10. Trials of the Automated Particle Counter for laboratory rearing of mosquito larvae
- Author
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Catherine M. Hunt, Erica I. Aviles, Ellen M. Dotson, Priscila Bascuñán, Mark Q. Benedict, and Rachel D. Rotenberry
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0106 biological sciences ,Life Cycles ,Physiology ,Anopheles gambiae ,Eggs ,Anopheles Gambiae ,Disease Vectors ,01 natural sciences ,Mosquitoes ,Automation ,0302 clinical medicine ,Larvae ,Medical Conditions ,Filter Paper ,Mosquito larvae ,Animal Cells ,Reproductive Physiology ,Medicine and Health Sciences ,Mathematics ,Flow Rate ,Multidisciplinary ,biology ,Physics ,Classical Mechanics ,Eukaryota ,Water stream ,Flow Cytometry ,Insects ,Laboratory Equipment ,Infectious Diseases ,Larva ,Physical Sciences ,Medicine ,Engineering and Technology ,Cellular Types ,Research Article ,2019-20 coronavirus outbreak ,animal structures ,Arthropoda ,Science ,Immune Cells ,030231 tropical medicine ,Immunology ,Antigen-Presenting Cells ,Equipment ,Aedes aegypti ,Fluid Mechanics ,Standard score ,Aedes Aegypti ,Continuum Mechanics ,03 medical and health sciences ,Animal science ,parasitic diseases ,Anopheles ,Animals ,Analysis of Variance ,fungi ,Organisms ,Biology and Life Sciences ,Fluid Dynamics ,Cell Biology ,biology.organism_classification ,Invertebrates ,Survival Analysis ,Insect Vectors ,010602 entomology ,Light intensity ,Species Interactions ,Laboratories ,Particle counter ,Zoology ,Entomology ,Developmental Biology - Abstract
As a means of obtaining reproducible and accurate numbers of larvae for laboratory rearing, we tested a large-particle flow-cytometer type device called the ‘Automated Particle Counter’ (APC). The APC is a gravity-fed, self-contained unit that detects changes in light intensity caused by larvae passing the detector in a water stream and controls dispensing by stopping the flow when the desired number has been reached. We determined the accuracy (number dispensed compared to the target value) and precision (distribution of number dispensed) of dispensing at a variety of counting sensitivity thresholds and larva throughput rates (larvae per second) using < 1-day old Anopheles gambiae and Aedes aegypti larvae. All measures were made using an APC algorithm called the ‘Smoothed Z-Score’ which allows the user to define how many standard deviations (Z scores) from the baseline light intensity a particle’s absorbance must exceed to register a count. We dispensed a target number of 100 An. gambiae larvae using Z scores from 2.5–8 and observed no difference among them in the numbers dispensed for scores from 2.5–6, however, scores of 7 and 8 under-counted (over-dispensed) larvae. Using a Z score ≤ 6, we determined the effect of throughput rate on the accuracy of the device to dispense An. gambiae larvae. For rates ≤ 98 larvae per second, the accuracy of dispensing a target of 100 larvae was - 2.29% ± 0.72 (95% CI of the mean) with a mode of 99 (49 of 348 samples). When using a Z score of 3.5 and rates ≤ 100 larvae per second, the accuracy of dispensing a target of 100 Ae. aegypti was - 2.43% ± 1.26 (95% CI of the mean) with a mode of 100 (6 of 42 samples). No effect on survival was observed on the number of An. gambiae first stage larvae that reached adulthood as a function of dispensing.
- Published
- 2020
11. Editorial: Processing, presentation, and recognition of T cell determinants: From molecular insights to clinical applications.
- Author
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James EA
- Subjects
- Epitopes, T-Lymphocytes, Antigen-Presenting Cells
- Abstract
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
- Published
- 2023
- Full Text
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12. Targeting and Specific Activation of Antigen‐Presenting Cells by Endogenous Antigen‐Loaded Nanoparticles Elicits Tumor‐Specific Immunity
- Author
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Huan Jin, Zhengzhi Zou, Jie Li, Haocai Chang, Qiu-Hong Wang, Da Xing, and Qian-Xia Yin
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General Chemical Engineering ,medicine.medical_treatment ,T cell ,General Physics and Astronomy ,Medicine (miscellaneous) ,02 engineering and technology ,010402 general chemistry ,01 natural sciences ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Immune system ,Cancer immunotherapy ,Antigen ,medicine ,General Materials Science ,lcsh:Science ,Antigen-presenting cell ,HSP70‐chaperoned polypeptides ,cancer immunotherapy ,Full Paper ,Chemistry ,Immunogenicity ,General Engineering ,CD8+/CD4+ T cells ,Immunotherapy ,Full Papers ,021001 nanoscience & nanotechnology ,codelivery system ,0104 chemical sciences ,medicine.anatomical_structure ,Cancer research ,antigen‐presenting cells ,lcsh:Q ,0210 nano-technology ,CD8 - Abstract
Immunotherapy has shown tremendous promise for improving cancer treatment. Unfortunately, antigen‐presenting cells (APCs) in cancer patients cannot effectively recognize and process tumor antigens to activate host immune responses. In this study, an approach is developed to improve cancer immunotherapy that utilizes endogenous antigen‐carrying nanoparticles (EAC‐NPs), which encompasses a set of antigens isolated from solid tumors and adjuvants. The EAC‐NPs specifically target APCs and subsequently result in enhanced T cell responses and improved antitumor efficacy. Mechanistic studies reveal that the EAC‐NPs enhance and prolong the presence of immune compounds in APCs, which ensure persistent antigen loading and stimulation, induce a rapid proliferation of CD4+ and CD8+ T cells, and significantly increase the ratios of intratumoral CD4+ T/Treg and CD8+ T/Treg. The work using nanotechnology provides a promising strategy in improving antitumor immunity by enhancing the immunogenicity and presentation of tumor self‐antigens for cancer immunotherapy., Endogenous antigen‐carrying nanoparticles are phagocytosed by antigen‐presenting cells (APCs) triggering antigen and Toll‐like receptor signaling. Then the APCs induce highly efficient differentiation of T cells toward helper T (CD4+) cells and cytotoxic T lymphocytes (CD8+) to finally generate potent antitumor immune responses. A promising strategy is established for cancer immunotherapy by enhancing the immunogenicity and presentation of tumor self‐antigens.
- Published
- 2019
13. Mesoporous silica nanoparticle-coated microneedle arrays for intradermal antigen delivery
- Author
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Juha Mönkäre, Alexander Kros, Wim Jiskoot, Guangsheng Du, Koen van der Maaden, Nico A. J. M. Sommerdijk, Paul H. H. Bomans, M. Reza Nejadnik, Bram Slütter, Joke A. Bouwstra, Jing Tu, and Materials and Interface Chemistry
- Subjects
animal structures ,Injections, Intradermal ,Ovalbumin ,Surface Properties ,Silicon dioxide ,Lipid Bilayers ,Antigen-Presenting Cells ,Pharmaceutical Science ,Nanoparticle ,Nanotechnology ,Human skin ,02 engineering and technology ,pH-sensitive microneedle arrays ,010402 general chemistry ,01 natural sciences ,chemistry.chemical_compound ,Humans ,Pharmacology (medical) ,Antigens ,Particle Size ,mesoporous silica nanoparticles ,Antigen-presenting cell ,Lipid bilayer ,Skin ,Pharmacology ,Drug Carriers ,Macrophages ,Organic Chemistry ,intradermal antigen delivery ,Hydrogen-Ion Concentration ,Mesoporous silica ,respiratory system ,Silicon Dioxide ,021001 nanoscience & nanotechnology ,lipid bilayer ,0104 chemical sciences ,Drug Liberation ,chemistry ,Needles ,Nanoparticles ,Molecular Medicine ,sense organs ,0210 nano-technology ,Drug carrier ,Porosity ,Ex vivo ,Research Paper ,Biotechnology ,Biomedical engineering - Abstract
Purpose To develop a new intradermal antigen delivery system by coating microneedle arrays with lipid bilayer-coated, antigen-loaded mesoporous silica nanoparticles (LB-MSN-OVA). Methods Synthesis of MSNs with 10-nm pores was performed and the nanoparticles were loaded with the model antigen ovalbumin (OVA), and coated with a lipid bilayer (LB-MSN-OVA). The uptake of LB-MSN-OVA by bone marrow-derived dendritic cells (BDMCs) was studied by flow cytometry. The designed LB-MSN-OVA were coated onto pH-sensitive pyridine-modified microneedle arrays and the delivery of LB-MSN-OVA into ex vivo human skin was studied. Results The synthesized MSNs demonstrated efficient loading of OVA with a maximum loading capacity of about 34% and the lipid bilayer enhanced the colloidal stability of the MSNs. Uptake of OVA loaded in LB-MSN-OVA by BMDCs was higher than that of free OVA, suggesting effective targeting of LB-MSN-OVA to antigen-presenting cells. Microneedles were readily coated with LB-MSN-OVA at pH 5.8, yielding 1.5 μg of encapsulated OVA per microneedle array. Finally, as a result of the pyridine modification, LB-MSN-OVA were effectively released from the microneedles upon piercing the skin. Conclusion Microneedle arrays coated with LB-MSN-OVA were successfully developed and shown to be suitable for intradermal delivery of the encapsulated protein antigen. Electronic supplementary material The online version of this article (doi:10.1007/s11095-017-2177-4) contains supplementary material, which is available to authorized users.
- Published
- 2017
14. Unique properties of thymic antigen-presenting cells promote epigenetic imprinting of alloantigen-specific regulatory T cells
- Author
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Jochen Huehn, Shimon Sakaguchi, Shohei Hori, Elmar Jaeckel, Anke Osterloh, Norbert Gerdes, Esther Lutgens, Matthias Hardtke-Wolenski, Stefan Floess, Michael Beckstette, Eirini Nikolouli, Aras Toker, Garima Garg, Robert Geffers, Naganari Ohkura, Takahisa Miyao, Helmholtz Centre for infection research, Inhoffenstr.7, 38124 Braunschweig, Germany., Medical Biochemistry, AII - Inflammatory diseases, and ACS - Atherosclerosis & ischemic syndromes
- Subjects
0301 basic medicine ,Male ,Isoantigens ,medicine.medical_treatment ,T-Lymphocytes, Regulatory ,regulatory T cells ,Epigenesis, Genetic ,Mice ,T-Lymphocyte Subsets ,Mice, Knockout ,Thymocytes ,Research Paper: Immunology ,FOXP3 ,Forkhead Transcription Factors ,hemic and immune systems ,Skin Transplantation ,Oncology ,Experimental pathology ,Immunology and Microbiology Section ,Female ,Signal Transduction ,CD40 Ligand ,Antigen-Presenting Cells ,Mice, Transgenic ,chemical and pharmacologic phenomena ,Thymus Gland ,alloantigen-specificity ,03 medical and health sciences ,Genomic Imprinting ,Immune system ,Immunity ,epigenetic modification ,medicine ,Animals ,Epigenetics ,Immune response ,CD40 Antigens ,Antigen-presenting cell ,business.industry ,Gene Expression Profiling ,Immunotherapy ,DNA Methylation ,Transplantation ,thymic APCs ,030104 developmental biology ,Gene Expression Regulation ,Immunology ,business ,Biomarkers - Abstract
// Garima Garg 1 , Eirini Nikolouli 1 , Matthias Hardtke-Wolenski 2 , Aras Toker 1 , Naganari Ohkura 3,4 , Michael Beckstette 1 , Takahisa Miyao 5 , Robert Geffers 6 , Stefan Floess 1 , Norbert Gerdes 7,8 , Esther Lutgens 7,9 , Anke Osterloh 10 , Shohei Hori 5 , Shimon Sakaguchi 3,4 , Elmar Jaeckel 2 and Jochen Huehn 1 1 Department of Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany 2 Department of Gastroenterology, Hepatology, Endocrinology, Hannover Medical School, Hannover, Germany 3 Department of Experimental Immunology, World Premier International Immunology Frontier Research Center, Osaka University, Suita, Japan 4 Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan 5 Laboratory for Immune Homeostasis, RIKEN Center for Integrative Medical Sciences, Yokohama City, Kanagawa, Japan 6 Genome Analytics, Helmholtz Centre for Infection Research, Braunschweig, Germany 7 Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany 8 Division of Cardiology, Pulmonology, and Vascular Medicine Medical Faculty, University Hospital Dusseldorf, Dusseldorf, Germany 9 Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, AZ, Amsterdam, The Netherlands 10 Department of Immunology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany Correspondence to: Jochen Huehn, email: // Keywords : regulatory T cells, thymic APCs, epigenetic modification, alloantigen-specificity, Immunology and Microbiology Section, Immune response, Immunity Received : October 15, 2016 Accepted : March 03, 2017 Published : March 15, 2017 Abstract Regulatory T cells (Tregs) are potential immunotherapeutic candidates to induce transplantation tolerance. However, stability of Tregs still remains contentious and may potentially restrict their clinical use. Recent work suggested that epigenetic imprinting of Foxp3 and other Treg-specific signature genes is crucial for stabilization of immunosuppressive properties of Foxp3 + Tregs, and that these events are initiated already during early stages of thymic Treg development. However, the mechanisms governing this process remain largely unknown. Here we demonstrate that thymic antigen-presenting cells (APCs), including thymic dendritic cells (t-DCs) and medullary thymic epithelial cells (mTECs), can induce a more pronounced demethylation of Foxp3 and other Treg-specific epigenetic signature genes in developing Tregs when compared to splenic DCs (sp-DCs). Transcriptomic profiling of APCs revealed differential expression of secreted factors and costimulatory molecules, however neither addition of conditioned media nor interference with costimulatory signals affected Foxp3 induction by thymic APCs in vitro . Importantly, when tested in vivo both mTEC- and t-DC-generated alloantigen-specific Tregs displayed significantly higher efficacy in prolonging skin allograft acceptance when compared to Tregs generated by sp-DCs. Our results draw attention to unique properties of thymic APCs in initiating commitment towards stable and functional Tregs, a finding that could be highly beneficial in clinical immunotherapy.
- Published
- 2017
15. Efficient generation of antigen-specific CTLs by the BAFF-activated human B Lymphocytes as APCs: a novel approach for immunotherapy
- Author
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Zhang Hui, Pan Ting, Gao Shilin, Li Linghua, Liu Chao, Luo Baohong, Chen Yingshi, Zhang Yiwen, and Su Lishi
- Subjects
0301 basic medicine ,tumor ,medicine.medical_treatment ,CD40 Ligand ,Antigen presentation ,Melanoma, Experimental ,Antigen-Presenting Cells ,HIV Infections ,Lymphocyte Activation ,HIV-immunotherapy ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,B-Cell Activating Factor ,Animals ,Humans ,Medicine ,Cytotoxic T cell ,B-cell activating factor ,CD86 ,B-Lymphocytes ,CD40 ,biology ,business.industry ,Immunotherapy ,APC ,Virus Latency ,CTL ,HEK293 Cells ,030104 developmental biology ,Oncology ,Immunology ,HIV-1 ,biology.protein ,BAFF ,business ,CD80 ,Research Paper ,T-Lymphocytes, Cytotoxic ,030215 immunology - Abstract
// Zhang Yiwen 1, 2, 3, * , Gao Shilin 1, 2, 3, * , Chen Yingshi 1, 2, 3 , Su Lishi 1, 2, 3 , Luo Baohong 1, 2, 3 , Liu Chao 1, 2, 3 , Li Linghua 4 , Pan Ting 1, 2, 3 , Zhang Hui 1, 2, 3 1 Institute of Human Virology, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China 2 Key Laboratory of Tropical Disease Control of Ministry of Education, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China 3 Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China 4 Department of Infectious Diseases, Guangzhou 8th People’s Hospital, Guangzhou, Guangdong, 510080, China * These authors have contributed equally to this work Correspondence to: Zhang Hui, email: zhangh92@mail.sysu.edu.cn Pan Ting, email: pant8@mail.sysu.edu.cn Keywords: B-lymphocytes, APC, BAFF, HIV-immunotherapy, tumor Received: April 07, 2016 Accepted: October 14, 2016 Published: October 21, 2016 ABSTRACT Efficient antigen presentation is indispensable for cytotoxic T lymphocyte (CTL)-mediated immunotherapy. B-lymphocytes propagated with CD40L have been developed as antigen-presenting cells (APCs), but this capacity needs further optimization. Here, we aimed to expand human B-lymphocytes on a large scale while maintaining their antigen-presenting ability by using both CD40L and B-cell activating factor (BAFF). The addition of BAFF enhanced the expansion efficiency and prolonged the culture time without causing apoptosis of the expanded B-cells. This method thus provided an almost unlimited source of cellular adjuvant to achieve sufficient expansion of CTLs in cases where several rounds of stimulation are required. We also showed that the addition of BAFF significantly enhanced the expression of major costimulatory molecules, CD80 and CD86. Subsequently, the antigen-presenting ability of the B-lymphocytes also increased. Consequently, these B-lymphocytes showed robust CTL responses to inhibit tumor growth after tumor-specific peptide pulses. A similar method induced potent antigen-specific CTL responses, which effectively eradicated human immunodeficiency virus type 1 (HIV-1) latency in CD4 T-lymphocytes isolated from patients receiving suppressive anti-retroviral therapy (ART). Together, our findings indicate that potent antigen-specific CTLs can be generated using BAFF-activated B-lymphocytes as APCs ex vivo. This approach can be applied for CTL-mediated immunotherapy in patients with cancers or chronic viral infections.
- Published
- 2016
16. Persistent lentivirus infection induces early myeloid suppressor cells expansion to subvert protective memory CD8 T cell response✰,✰✰
- Author
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Zhiwu Tan, Li Liu, Zhenglong Du, Hang Ying Tang, Zhiwei Chen, Qingqing Lin, Hauyee Kwok, Kang Liu, Kwok-Yung Yuen, Jun Fang, Ka-Yi Kwan, Kenji Nishiura, Jie Peng, Jianguo Liang, Jiaze Sun, and Hui Wang
- Subjects
0301 basic medicine ,Myeloid ,lcsh:Medicine ,HIV Infections ,CD8-Positive T-Lymphocytes ,Lymphocyte Activation ,law.invention ,Mice ,0302 clinical medicine ,law ,Cytotoxic T cell ,T cell exhaustion ,lcsh:R5-920 ,Antigen Presentation ,biology ,General Medicine ,Viral Load ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Host-Pathogen Interactions ,Lentivirus ,Female ,lcsh:Medicine (General) ,Immunocompetence ,Research Paper ,Persistent virus infection ,T cell ,MDSCs ,Antigen-Presenting Cells ,Mice, Transgenic ,Lymphocyte Depletion ,General Biochemistry, Genetics and Molecular Biology ,Immunomodulation ,03 medical and health sciences ,Acquired immunodeficiency syndrome (AIDS) ,medicine ,Animals ,Humans ,Memory cd8 t cell response ,Myeloid-Derived Suppressor Cells ,lcsh:R ,Viral Vaccines ,Dendritic Cells ,biology.organism_classification ,medicine.disease ,Disease Models, Animal ,030104 developmental biology ,Apoptosis ,Immunology ,HIV-1 ,Lentivirus Infections ,Suppressor ,Vaccine ,Immunologic Memory ,Biomarkers ,CD8 - Abstract
Background Memory CD8+ T cell responses play an essential role in protection against persistent infection. However, HIV-1 evades vaccine-induced memory CD8+ T cell response by mechanisms that are not fully understood. Methods We analyzed the temporal dynamics of CD8+ T cell recall activity and function during EcoHIV infection in a potent PD1-based vaccine immunized immunocompetent mice. Findings Upon intraperitoneal EcoHIV infection, high levels of HIV-1 GAG-specific CD8+ T lymphocytes recall response reduced EcoHIV-infected cells significantly. However, this protective effect diminished quickly after seven days, followed by a rapid reduction of GAG-specific CD8+ T cell number and activity, and viral persistence. Mechanistically, EcoHIV activated dendritic cells (DCs) and myeloid cells. Myeloid cells were infected and rapidly expanded, exhibiting elevated PD-L1/-L2 expression and T cell suppressive function before day 7, and were resistant to CD8+ T cell-mediated apoptosis. Depletion of myeloid-derived suppressor cells (MDSCs) reduced EcoHIV infection and boosted T cell responses. Interpretation This study provides an overview of the temporal interplay of persistent virus, DCs, MDSCs and antigen-specific CD8+ T cells during acute infection. We identify MDSCs as critical gatekeepers that restrain antiviral T cell memory responses, and highlight MDSCs as an important target for developing effective vaccines against chronic human infections. Funding Hong Kong Research Grant Council (T11–709/18-N, HKU5/CRF/13G), General Research Fund (17122915 and 17114114), Hong Kong Health and Medical Research Fund (11100752, 14130582, 16150662), Grant RGC-ANR A-HKU709/14, the San-Ming Project of Medicine (SZSM201512029), University Development Fund of the University of Hong Kong and Li Ka Shing Faculty of Medicine Matching Fund to HKU AIDS Institute.
- Published
- 2020
17. B lymphocytes as direct antigen-presenting cells for anti-tumor DNA vaccines
- Author
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Viswa Teja Colluru and Douglas G. McNeel
- Subjects
CD4-Positive T-Lymphocytes ,DNA vaccine ,0301 basic medicine ,Antigen-Presenting Cells ,CD8-Positive T-Lymphocytes ,Biology ,Cancer Vaccines ,DNA vaccination ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Plasmid ,Antigen ,Cell Line, Tumor ,Vaccines, DNA ,Animals ,Humans ,Cytotoxic T cell ,Immune response ,Antigen-presenting cell ,Mice, Knockout ,Antigen Presentation ,B-Lymphocytes ,B cells ,Immunogenicity ,Research Paper: Immunology ,Immunity ,Cross-presentation ,DNA ,Dendritic Cells ,Virology ,Coculture Techniques ,3. Good health ,Mice, Inbred C57BL ,direct presentation ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Immunology ,Immunology and Microbiology Section ,Sarcoma, Experimental ,Plasmids - Abstract
// Viswa Teja Colluru 1,2 and Douglas G. McNeel 1,2 1 Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA 2 Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USA Correspondence to: Douglas G. McNeel, email: // Keywords : DNA vaccine, B cells, dendritic cells, direct presentation, Immunology and Microbiology Section, Immune response, Immunity Received : July 26, 2016 Accepted : September 16, 2016 Published : September 21, 2016 Abstract In spite of remarkable preclinical efficacy, DNA vaccination has demonstrated low immunogenicity in humans. While efforts have focused on increasing cross-presentation of DNA-encoded antigens, efforts to increase DNA vaccine immunogenicity by targeting direct presentation have remained mostly unexplored. In these studies, we compared the ability of different APCs to present antigen to T cells after simple co-culture with plasmid DNA. We found that human primary peripheral B lymphocytes, and not monocytes or in vitro derived dendritic cells (DCs), were able to efficiently encode antigen mRNA and expand cognate tumor antigen-specific CD8 T cells ex vivo . Similarly, murine B lymphocytes co-cultured with plasmid DNA, and not DCs, were able to prime antigen-specific T cells in vivo. Moreover, B lymphocyte-mediated presentation of plasmid antigen led to greater Th1-biased immunity and was sufficient to elicit an anti-tumor effect in vivo . Surprisingly, increasing plasmid presentation by B cells, and not cross presentation of peptides by DCs, further augmented traditional plasmid vaccination. Together, these data suggest that targeting plasmid DNA to B lymphocytes, for example through transfer of ex vivo plasmidloaded B cells, may be novel means to achieve greater T cell immunity from DNA vaccines.
- Published
- 2016
18. Expression of PD-1 on CD4+ T cells in peripheral blood associates with poor clinical outcome in non-small cell lung cancer
- Author
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Junjia Zhu, Jianhong Zhang, Chandra P. Belani, Yaxian Kong, Hong Zheng, Xin Liu, Monika Joshi, Shawn J. Rice, Liuluan Zhu, and Matthias Wagman
- Subjects
CD4-Positive T-Lymphocytes ,Male ,0301 basic medicine ,Oncology ,Lung Neoplasms ,Programmed Cell Death 1 Receptor ,Kaplan-Meier Estimate ,Pembrolizumab ,NSCLC ,B7-H1 Antigen ,Antineoplastic Agents, Immunological ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,PD-1 ,Aged, 80 and over ,Middle Aged ,Flow Cytometry ,Prognosis ,Treatment Outcome ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Female ,Nivolumab ,Research Paper ,medicine.medical_specialty ,T cell ,T cells ,Antigen-Presenting Cells ,Disease-Free Survival ,03 medical and health sciences ,Immune system ,Internal medicine ,Blocking antibody ,Biomarkers, Tumor ,medicine ,Humans ,Lung cancer ,Antigen-presenting cell ,Aged ,Neoplasm Staging ,business.industry ,Cell Membrane ,Cancer ,peripheral blood ,medicine.disease ,030104 developmental biology ,Immunology ,business ,Follow-Up Studies - Abstract
// Hong Zheng 1, * , Xin Liu 1, * , Jianhong Zhang 1 , Shawn J. Rice 1 , Matthias Wagman 1 , Yaxian Kong 2 , Liuluan Zhu 2 , Junjia Zhu 1 , Monika Joshi 1 , Chandra P. Belani 1 1 Penn State Hershey Cancer Institute, Penn State College of Medicine, Hershey, PA, USA 2 Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China * These authors have contributed equally to this work Correspondence to: Chandra Belani, e-mail: cbelani@psu.edu Keywords: PD-1, peripheral blood, T cells, prognosis, NSCLC Received: February 12, 2016 Accepted: April 13, 2016 Published: May 12, 2016 ABSTRACT Recent success of using agents inhibiting the major immune check point, programmed cell death-1 (PD-1) pathway, offers a great promise for effective cancer therapy. Two blocking antibodies for PD-1, nivolumab and pembrolizumab have recently been approved for treating advanced recurrent non-small cell lung cancer (NSCLC). Activation of PD-1 on T cells and PD-L1 on tumor cells or antigen presenting cells leads to T cell exhaustion and ultimately tumor growth. In this study, we performed flow cytometry analysis of peripheral blood samples collected from patients with advanced NSCLC at initial diagnosis. We report that surface expression of PD-1 on CD4 + T cells has a prognostic value in NSCLC patients, as high expression of PD-1 is associated with a shorter progression-free survival and overall survival. Importantly, we also found that high PD-1 expression on peripheral CD4 + T cells is associated with inferior clinical response in a subset of patients who received anti-PD-L1 treatment, indicating a potential predictive value of this marker. This work highlights the potential of a non-invasive and effective method to determine prognostic and predictive biomarkers for inhibiting the PD-1 pathway in NSCLC patients.
- Published
- 2016
19. Artificial antigen-presenting cells expressing AFP158-166 peptide and interleukin-15 activate AFP-specific cytotoxic T lymphocytes
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Tong Liu, Zhixiang Zhang, Longhao Sun, Xianghui He, Ruoyu Jiang, Li Lu, and Hao Guo
- Subjects
0301 basic medicine ,Antigen-Presenting Cells ,Epitopes, T-Lymphocyte ,chemical and pharmacologic phenomena ,interleukin-15 ,Mice, SCID ,cytotoxic T lymphocytes ,Immunotherapy, Adoptive ,03 medical and health sciences ,alpha-fetoprotein ,Mice ,Random Allocation ,0302 clinical medicine ,Artificial antigen presenting cells ,Immune system ,Antigens, Neoplasm ,Mice, Inbred NOD ,Cell Line, Tumor ,HLA-A2 Antigen ,Cytotoxic T cell ,Medicine ,Animals ,Humans ,Immune response ,CD86 ,Tumor microenvironment ,business.industry ,Liver Neoplasms ,Research Paper: Immunology ,Immunity ,Interleukin ,hemic and immune systems ,Hep G2 Cells ,Xenograft Model Antitumor Assays ,digestive system diseases ,Peptide Fragments ,030104 developmental biology ,Oncology ,Interleukin 15 ,030220 oncology & carcinogenesis ,artificial antigen-presenting cells ,Immunology ,Immunology and Microbiology Section ,alpha-Fetoproteins ,business ,adoptive immunotherapy ,CD80 ,T-Lymphocytes, Cytotoxic - Abstract
// Longhao Sun 1 , Hao Guo 1 , Ruoyu Jiang 1 , Li Lu 1 , Tong Liu 1 , Zhixiang Zhang 1 and Xianghui He 1 1 Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China Correspondence to: Xianghui He, email: // Keywords : artificial antigen-presenting cells, alpha-fetoprotein, interleukin-15, cytotoxic T lymphocytes, adoptive immunotherapy, Immunology and Microbiology Section, Immune response, Immunity Received : November 30, 2015 Accepted : March 14, 2016 Published : March 19, 2016 Abstract Professional antigen-presenting cells (APCs) are potent generators of tumor antigen-specific cytotoxic T lymphocytes (CTLs) for adoptive immunotherapy; however, generation of APCs is cumbersome, expensive, and subject to the tumor microenvironment. Artificial APCs (aAPCs) have been developed as a cost-effective alternative to APCs. We developed a cellular aAPC that efficiently generated alpha-fetoprotein (AFP)-specific CTLs. We genetically modified the human B cell lymphoma cell line BJAB with a lentiviral vector to establish an aAPC called BA15. The expression of AFP 158-166 -HLA-A*02:01 complex, CD80, CD86, and interleukin (IL)-15 in BA15 cells was assessed. The efficiency of BA15 at generating AFP-specific CTLs and the specific cytotoxicity of CTLs against AFP+ cells were also determined. BA15 cells expressed high levels of AFP 158-166 peptide, HLA-A2, CD80, CD86, and IL-15. BA15 cells also exhibited higher efficiency in generating AFP-specific CTLs than did dendritic cells. These CTLs had greater cytotoxicity against AFP+ hepatocellular carcinoma cells than did CTLs obtained from dendritic cells in vitro and in vivo . Our novel aAPC system could provide a robust platform for the generation of functional AFP-specific CTLs for adoptive immunotherapy of hepatocellular carcinoma.
- Published
- 2016
20. Inadequate activation of the HBsAg-specific Th cells by APCs leads to hyporesponsiveness to HBsAg vaccine in B10.S mice
- Author
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Jing Wang, Wei Zhu, ZhiHui Lv, Bin Wang, Di Qu, Shu-Hui Sun, Xiaofei Li, Jing Xu, and Rui He
- Subjects
Receptors, CCR7 ,HBsAg ,Hepatitis B vaccine ,T-Lymphocytes ,Plasma Cells ,Immunology ,Antigen-Presenting Cells ,chemical and pharmacologic phenomena ,Injections, Intramuscular ,Mice ,Antigen ,Cell Movement ,Animals ,Immunology and Allergy ,Medicine ,Hepatitis Antibodies ,Lymphocyte Count ,CD40 Antigens ,Antigen-presenting cell ,Pharmacology ,Hepatitis B Surface Antigens ,CD40 ,biology ,business.industry ,Toxoid ,virus diseases ,hemic and immune systems ,Dendritic Cells ,Hepatitis B ,medicine.disease ,Virology ,Mice, Inbred C57BL ,Immunoglobulin G ,biology.protein ,B7-2 Antigen ,business ,Cell activation ,Research Paper - Abstract
Hepatitis B can be effectively prevented by hepatitis B vaccination. However, hyporesponse to the hepatitis B vaccine has been found in both human and inbred mice with particular MHC alleles or haplotypes, but the mechanisms underlying this poor response remains elusive. In the present study, we investigated the mechanisms underlying the hyporesponse to hepatitis B vaccination using B10.S-H2s/SgMcdJ (B10.S, H-2(s), poor responder) and C57BL/10J (B10, H-2(b), good responder) mice. We observed that the B10.S mice displayed a hyporesponse to HBsAg vaccine but a normal response to 3 other foreign antigens (influenza A (H1N1) 2009 monovalent vaccine, tetanus toxoid and ovalbumin). In B10.S mice immunized with HBsAg, the levels of serum anti-HBs IgG, the number of HBsAg-specific IgG-secreting plasma cells and HBsAg-specific Th cells were considerably lower than that in B10 mice. Further, the findings of the insufficient maturation (CD86), co-stimulation (CD40) and migration (CCR7) activities of DCs together with the inadequate activation of the HBsAg-specific Th cells by APCs were identified as part of the reason for the HBsAg hyporesponse in B10.S mice, which supports the hypothesis that measures aimed at promoting the maturation, co-stimulation or migration of APCs to enhance Th cell activation may be a useful strategy for the development of new hepatitis B vaccines.
- Published
- 2015
21. Effect of IL-18 on the Expansion and Phenotype of Human Natural Killer Cells: Application to Cancer Immunotherapy
- Author
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Yoshimasa Tanaka, Yuka Harada, Katsumi Nakatomi, Asuka Kumagai, Haruki Okamura, Yoichi Nakamura, Hiroshi Mukae, Hiroyuki Yamaguchi, Kengo Shiraishi, Shota Fukami, Hiroaki Senju, and Mitsuhiro Nakamura
- Subjects
0301 basic medicine ,Adult ,medicine.medical_treatment ,Antigen-Presenting Cells ,NK cells ,Biology ,Applied Microbiology and Biotechnology ,Immunophenotyping ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Cancer immunotherapy ,Neoplasms ,PD-1 ,medicine ,Humans ,Antigen-presenting cell ,Molecular Biology ,immune checkpoint ,Ecology, Evolution, Behavior and Systematics ,CD86 ,Innate immune system ,Interleukin-18 ,Cell Biology ,Acquired immune system ,Killer Cells, Natural ,030104 developmental biology ,Cytokine ,Cancer research ,Interleukin-2 ,Immunotherapy ,K562 Cells ,CD80 ,IL-18 ,030215 immunology ,Developmental Biology ,Research Paper - Abstract
When pathogenic stresses are recognized by innate immune cells, inflammasomes are assembled and caspase-1 is activated, resulting in the conversion of pro-IL-18 into mature IL-18. Because natural killer (NK) cells express IL-18 receptors, IL-18 may play roles in immune functions of NK cells. In the present study, we examined the effect of IL-18 on NK cells derived from lung cancer patients and healthy adult volunteers. When peripheral blood NK cells were stimulated with IL-2, the cells formed clusters beginning on day 5-6 and proliferated thereafter, in which the number of NK cells increased by 10-fold in 10 days. When IL-18 was added, cell clusters were observed as early as on day 4 and NK cells proliferated vigorously. On day 10, the expansion rate was 56-fold on average, showing that IL-18 promoted the expansion of NK cells. It was also notable that IL-18 enhanced the expression of CD80, CD86, HLA-DR and HLA-DQ on NK cells, suggesting that IL-18 conferred NK cells an APC-like phenotype. When cellular cytotoxicity was determined, APC-like NK cells efficiently killed tumor cells and anti-tumor activity was augmented by the addition of tumor antigen-specific mAbs. In addition, IFN-γ was produced by APC-like NK cells in response to tumor cells, and the cytokine production was further enhanced by mAbs. Taken together, IL-18 not only promoted the expansion of NK cells, but also changed the phenotype of NK cells. IL-2/IL-18-induced NK cells might, therefore, serve as a bridge between innate immunity and adaptive immunity and be useful for cancer immunotherapy.
- Published
- 2017
22. Culling of APCs by inflammatory cell death pathways restricts TIM3 and PD-1 expression and promotes the survival of primed CD8 T cells
- Author
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Kristina Wachholz, Rajen Patel, Lakshmi Krishnan, Subash Sad, Kwangsin Kim, and Bojan Shutinoski
- Subjects
0301 basic medicine ,Salmonella ,Programmed cell death ,Cell Survival ,Programmed Cell Death 1 Receptor ,Antigen-Presenting Cells ,Priming (immunology) ,CD8-Positive T-Lymphocytes ,Biology ,medicine.disease_cause ,03 medical and health sciences ,Cross-Priming ,Inflammatory cell ,medicine ,Animals ,Cytotoxic T cell ,Hepatitis A Virus Cellular Receptor 2 ,Molecular Biology ,Inflammation ,Original Paper ,Innate immune system ,Cell Death ,NF-kappa B ,Dendritic Cells ,Cell Biology ,Mice, Inbred C57BL ,030104 developmental biology ,Caspases ,Receptor-Interacting Protein Serine-Threonine Kinases ,Immunology ,Mitogen-Activated Protein Kinases ,Signal transduction ,CD8 ,Interleukin-1 ,Signal Transduction - Abstract
We evaluated the impact of premature cell death of antigen-presenting cells (APCs) by Caspase-1- and RipK3-signaling pathways on CD8+ T-cell priming during infection of mice with Salmonella typhimurium (ST). Our results indicate that Caspase1 and RipK3 synergize to rapidly eliminate infected APCs, which does not influence the initial activation of CD8+ T cells. However, the maintenance of primed CD8+ T cells was greatly compromised when both these pathways were disabled. Caspase-1- and RipK3-signaling did not influence NF-κB signaling in APCs, but synergized to promote processing of IL-1 and IL-18. Combined deficiency of Caspase1 and RipK3 resulted in compromised innate immunity and accelerated host fatality due to poor processing of IL-18. In contrast, synergism in cell death by Caspase-1- and RipK3 resulted in restriction of PD-1 and TIM3 expression on primed CD8+ T cells, which promoted the survival of activated CD8+ T cells.
- Published
- 2017
23. Activation of NK cells by HIV-specific ADCC antibodies
- Author
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Gamze Isitman, Marjon Navis, Ivan Stratov, Vijaya Madhavi, Robert De Rose, Stephen J. Kent, Amy W. Chung, and Leia Wren
- Subjects
Adult ,HIV Antigens ,Immunology ,Antigen-Presenting Cells ,chemical and pharmacologic phenomena ,HIV Antibodies ,Biology ,Epitope ,Antigen ,Annexin ,Humans ,Immunology and Allergy ,HIV vaccine ,Antigen-presenting cell ,Cells, Cultured ,Pharmacology ,Antibody-dependent cell-mediated cytotoxicity ,Antibody-Dependent Cell Cytotoxicity ,virus diseases ,Virology ,Killer Cells, Natural ,HIV-1 ,biology.protein ,Antibody ,Research Paper ,Granulocytes - Abstract
HIV-specific ADCC antibodies could play a role in providing protective immunity. We have developed a whole blood ADCC assay that measures NK cell activation in response to HIV peptide epitopes. These HIV peptide-specific ADCC responses are associated with escape from immune recognition and slower progression of HIV infection and represent interesting HIV vaccine antigens. However, the mechanism by which these epitopes are expressed and whether or not they induce NK-mediated killing of cells expressing such peptide-antigens is not understood. Herein, we show that fluorescent-tagged ADCC peptide epitopes associate with blood granulocytes. The peptide-associated granulocytes become a specific target for antibody-mediated killing, as shown by enhanced expression of apoptosis marker Annexin and reduction in cell numbers. When HIV Envelope gp140 protein is utilized in the ADCC assay, we detected binding to its ligand, CD4. During the incubation, cells co-expressing gp140 and CD4 reduce in number. We also detected increasing Annexin expression in these cells. These data indicate that blood cells expressing HIV-specific ADCC epitopes are targeted for killing by NK cells in the presence of ADCC antibodies in HIV+ plasma and provide a clearer framework to evaluate these antigens as vaccine candidates.
- Published
- 2013
24. Emergence, origin, and function of neutrophil–dendritic cell hybrids in experimentally induced inflammatory lesions in mice
- Author
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Akira Takashima, Robert Blumenthal, Yi Yao, Kristen Page, Takashi Okamoto, Shuo Geng, Ran Lu, Nicole L. Ward, Toru Miyazaki, and Hironori Matsushima
- Subjects
Neutrophils ,Blotting, Western ,Green Fluorescent Proteins ,Immunology ,Antigen presentation ,Plenary Paper ,Antigen-Presenting Cells ,CD11c ,Inflammation ,Hybrid Cells ,Peritonitis ,Biology ,Biochemistry ,Immunophenotyping ,Mice ,Escherichia coli ,medicine ,Animals ,Antigen-presenting cell ,Lung ,Cells, Cultured ,Escherichia coli Infections ,Skin ,Mice, Knockout ,CD86 ,Antigen Presentation ,Innate immune system ,Histocompatibility Antigens Class II ,Cell Differentiation ,Dendritic Cells ,Cell Biology ,Hematology ,Dendritic cell ,Flow Cytometry ,Mice, Inbred C57BL ,Disease Models, Animal ,Cytokines ,medicine.symptom ,Biomarkers ,CD80 - Abstract
Although unusual neutrophils expressing major histocompatibility complex class II (MHC II) and costimulatory molecules have been detected at inflammatory sites in mice and humans, their identity, origin, and function remain unclear. We have demonstrated that, when cultured with granulocyte macrophage-colony-stimulating factor, neutrophils can give rise to a unique hybrid population exhibiting dual phenotypic and functionality of neutrophils and dendritic cells (DCs). Here we report that hybrid cells expressing surface markers of neutrophils (Ly6G, L-selectin, CXC chemokines receptor 2, and 7/4) and DCs (CD11c, MHC II, CD80, and CD86) become detectable in the peritoneal cavity, skin, lung, and lymph nodes under inflammatory conditions. Importantly, 20% to 30% of the adoptively transferred neutrophils acquired CD11c and MHC II expression when recovered from inflammatory lesions, demonstrating neutrophil → hybrid conversion in living animals. Using Escherichia coli strains expressing green fluorescent protein and ovalbumin, we further show hybrids play dual protective roles by rapidly clearing bacteria and presenting bacterial antigens to CD4 T cells. These results indicate that some of the neutrophils recruited to inflammatory lesions can differentiate into neutrophil-DC hybrids, thus challenging the classic view of neutrophils as terminally differentiated leukocytes destined to die or to participate primarily in host innate immunity.
- Published
- 2013
25. Neutrophil differentiation into a unique hybrid population exhibiting dual phenotype and functionality of neutrophils and dendritic cells
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Nobuyasu Mayuzumi, Paul Kotol, Richard L. Gallo, Shuo Geng, Hironori Matsushima, Ran Lu, Benjamin J. Chojnacki, Yi Yao, Takashi Okamoto, Akira Takashima, and Toru Miyazaki
- Subjects
Podosome ,Neutrophils ,Blotting, Western ,Immunology ,Antigen presentation ,Population ,Plenary Paper ,Antigen-Presenting Cells ,CD11c ,Hybrid Cells ,Biology ,Biochemistry ,Mice ,Phagocytosis ,Neutrophil differentiation ,Animals ,Antigen-presenting cell ,education ,Cells, Cultured ,Oligonucleotide Array Sequence Analysis ,Mice, Knockout ,Antigen Presentation ,education.field_of_study ,MHC class II ,Gene Expression Profiling ,Cell Differentiation ,Dendritic Cells ,Cell Biology ,Hematology ,Neutrophil extracellular traps ,Flow Cytometry ,Molecular biology ,Cell biology ,Mice, Inbred C57BL ,Phenotype ,biology.protein ,Cytokines ,Biomarkers - Abstract
Neutrophils have been reported to acquire surface expression of MHC class II and co-stimulatory molecules as well as T-cell stimulatory activities when cultured with selected cytokines. However, cellular identity of those unusual neutrophils showing antigen presenting cell (APC)-like features still remains elusive. Here we show that both immature and mature neutrophils purified from mouse bone marrow differentiate into a previously unrecognized "hybrid" population showing dual properties of both neutrophils and dendritic cells (DCs) when cultured with granulocyte macrophage-colony-stimulating factor but not with other tested growth factors. The resulting hybrid cells express markers of both neutrophils (Ly6G, CXCR2, and 7/4) and DCs (CD11c, MHC II, CD80, and CD86). They also exhibit several properties typically reserved for DCs, including dendritic morphology, probing motion, podosome formation, production of interleukin-12 and other cytokines, and presentation of various forms of foreign protein antigens to naïve CD4 T cells. Importantly, they retain intrinsic abilities of neutrophils to capture exogenous material, extrude neutrophil extracellular traps, and kill bacteria via cathelicidin production. Not only do our results reinforce the notion that neutrophils can acquire APC-like properties, they also unveil a unique differentiation pathway of neutrophils into neutrophil-DC hybrids that can participate in both innate and adaptive immune responses.
- Published
- 2013
26. Immuno-potentiating pathway of HBsAg-HBIG immunogenic complex visualized
- Author
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Bing Wu, Shuang Wang, Bo Wang, Yiwei Zhong, Shuang Geng, Hu Liu, Di Qu, Xiaoping Xie, Yumei Wen, Xuan-Yi Wang, and Bin Wang
- Subjects
0301 basic medicine ,CD4-Positive T-Lymphocytes ,HBsAg ,T cell ,Immunology ,Antigen presentation ,Antigen-Presenting Cells ,Immunoglobulins ,Antigen-Antibody Complex ,CD8-Positive T-Lymphocytes ,03 medical and health sciences ,Immunology and Allergy ,Medicine ,Animals ,Antigen-presenting cell ,Late endosome ,Pharmacology ,Hepatitis B Surface Antigens ,business.industry ,Cross-presentation ,Virology ,Research Papers ,Endocytosis ,Mice, Inbred C57BL ,Protein Transport ,030104 developmental biology ,medicine.anatomical_structure ,Female ,business ,Viral load ,CD8 - Abstract
Chronic viral hepatitis B (CHB) is a major global health problem. A therapeutic vaccine for CHB comprised of yeast-derived recombinant HBsAg-anti-HBs immunogenic complexes (YIC) has been devloped by us. A series of clinical trials has shown its therapeutic efficacy in decreasing HBV viral load and converting serum HBeAg-positive to anti-HBe-positive status in a subpopulation of CHB patients. Herein, we present a study of the immuno-potentiating mechanisms of YIC revealed by live-cell imaging technology. We studied internalization and dissociation of YIC in cells in vitro, and antigen presentation and T cell stimulation in mice. We found that after YIC was internalized via the Fcγ receptors (FcγR) of antigen presenting cells, it was subsequently transferred through early and late endosomal into lysosomal compartments. The dissociation of YIC was mainly observed in the late endosome. Furthermore when YIC were injected into mice, the populations of IFN-γ- and TNF-α-producing CD8+ and CD4+ T cells were higher in the YIC group than in controls receiving antigen or antibody alone. These observations supplement the known mechanisms of YIC action as a therapeutic vaccine for CHB.
- Published
- 2015
27. Epithelial crosstalk at the microbiota-mucosal interface
- Author
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Marjolein Meijerink, Jerry M. Wells, Oriana Rossi, and Peter van Baarlen
- Subjects
factor-kappa-b ,Colloquium Papers ,Inflammation ,Biology ,growth-factor-beta ,digestive system ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immune system ,Intestinal mucosa ,intestinal dendritic cells ,medicine ,Immune Tolerance ,Animals ,Humans ,antigen-presenting cells ,paneth cells ,Host-Microbe Interactomics ,lamina propria ,Intestinal Mucosa ,Antigen-presenting cell ,Receptor ,Symbiosis ,030304 developmental biology ,stromal cells ,0303 health sciences ,Multidisciplinary ,crohns-disease ,Pattern recognition receptor ,Intestinal epithelium ,030220 oncology & carcinogenesis ,Receptors, Pattern Recognition ,toll-like receptor-4 ,Immunology ,Immunoglobulin A, Secretory ,WIAS ,immune-response ,Metagenome ,medicine.symptom ,Signal transduction ,Signal Transduction - Abstract
This article provides an overview of how intestinal epithelial cells (IEC) recognize commensals and how they maintain host-bacterial symbiosis. Endocrine, goblet cells, and enterocytes of the intestinal epithelium express a range of pattern recognition receptors (PRR) to sense the presence of microbes. The best characterized are the Toll-like receptors (TLR) and nucleotide oligomerization domain-like receptors (NLR), which play a key role in pathogen recognition and the induction of innate effectors and inflammation. Several adaptations of PRR signaling have evolved in the gut to avoid uncontrolled and potentially destructive inflammatory responses toward the resident microbiota. PRR signaling in IEC serve to maintain the barrier functions of the epithelium, including the production of secretory IgA (sIgA). Additionally, IECs play a cardinal role in setting the immunosuppressive tone of the mucosa to inhibit overreaction against innocuous luminal antigens. This includes regulation of dendritic cells (DC), macrophage and lymphocyte functions by epithelial secreted cytokines. These immune mechanisms depend heavily on IEC recognition of microbes and are consistent with several studies in knockout mice that demonstrate TLR signaling in the epithelium has a profoundly beneficial role in maintaining homeostasis.
- Published
- 2011
28. Modulation of CD4+ T-cell activation by CD95 co-stimulation
- Author
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Maren Paulsen, Dietrich Kabelitz, Sabine Adam-Klages, Ottmar Janssen, B. Mathew, S Valentin, Uwe Bertsch, Inna N. Lavrik, and Peter H. Krammer
- Subjects
CD4-Positive T-Lymphocytes ,Fas Ligand Protein ,CD3 Complex ,medicine.medical_treatment ,CD3 ,Receptors, Antigen, T-Cell ,Antigen-Presenting Cells ,Cell Cycle Proteins ,chemical and pharmacologic phenomena ,Biology ,Lymphocyte Activation ,Downregulation and upregulation ,Co-stimulation ,medicine ,Guanine Nucleotide Exchange Factors ,Humans ,Cytotoxic T cell ,fas Receptor ,Phosphorylation ,Molecular Biology ,Transcription factor ,Cell Proliferation ,Mitogen-Activated Protein Kinase Kinases ,Original Paper ,T-cell receptor ,Antibodies, Monoclonal ,Nuclear Proteins ,hemic and immune systems ,Cell Biology ,Cell biology ,Immobilized Proteins ,Cytokine ,Caspases ,biology.protein ,Cytokines ,Signal transduction ,Signal Transduction - Abstract
CD95 is a dual-function receptor that exerts pro- or antiapoptotic effects depending on the cellular context, the state of activation, the signal threshold and the mode of ligation. In this study, we report that CD95 engagement modulates TCR/CD3-driven signaling pathways in resting T lymphocytes in a dose-dependent manner. While high doses of immobilized CD95 agonists silence T cells, lower concentrations augment activation and proliferation. We analyzed the co-stimulatory capacity of CD95 in detail in resting human CD4(+) T cells, and demonstrate that low-dose ligand-induced co-internalization of CD95 and TCR/CD3 complexes enables non-apoptotic caspase activation, the prolonged activation of MAP kinases, the upregulation of antiapoptotic proteins associated with apoptosis resistance, and the activation of transcription factors and cell-cycle regulators for the induction of proliferation and cytokine production. We propose that the levels of CD95L on antigen-presenting cells (APCs), neighboring T cells or epithelial cells regulate inhibitory or co-stimulatory CD95 signaling, which in turn is crucial for fine-tuning of primary T-cell activation.
- Published
- 2010
29. A panel of human cell-based artificial APC enables the expansion of long-lived antigen-specific CD4+ T cells restricted by prevalent HLA-DR alleles
- Author
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Makito Tanaka, Naoto Hirano, Marcus O. Butler, Alla Berezovskaya, Matthew I. Milstein, Sascha Ansén, Osamu Imataki, Lee M. Nadler, Genita Metzler, and Mary M. Mooney
- Subjects
CD4-Positive T-Lymphocytes ,T cell ,Immunology ,Antigen-Presenting Cells ,FOXP3 ,HLA-DR Antigens ,General Medicine ,Human leukocyte antigen ,CD8-Positive T-Lymphocytes ,Biology ,Cell Line ,CTL ,medicine.anatomical_structure ,Antigen ,medicine ,Humans ,Immunology and Allergy ,Cytotoxic T cell ,Original Research Papers ,Alleles ,CD8 ,CD80 - Abstract
Many preclinical experiments have attested to the critical role of CD4(+) T cell help in CD8(+) cytotoxic T lymphocyte (CTL)-mediated immunity. Recent clinical trials have demonstrated that reinfusion of CD4(+) T cells can induce responses in infectious diseases and cancer. However, few standardized and versatile systems exist to expand antigen-specific CD4(+) T(h) for clinical use. K562 is a human erythroleukemic cell line, which lacks expression of HLA class I and class II, invariant chain and HLA-DM but expresses adhesion molecules such as intercellular adhesion molecule-1 and leukocyte function-associated antigen-3. With this unique immunologic phenotype, K562 has been tested in clinical trials of cancer immunotherapy. Previously, we created a K562-based artificial antigen-presenting cell (aAPC) that generates ex vivo long-lived HLA-A2-restricted CD8(+) CTL with a central/effector memory phenotype armed with potent effector function. We successfully generated a clinical version of this aAPC and conducted a clinical trial where large numbers of anti-tumor CTL are reinfused to cancer patients. In this article, we shifted focus to CD4(+) T cells and developed a panel of novel K562-derived aAPC, where each expresses a different single HLA-DR allele, invariant chain, HLA-DM, CD80, CD83 and CD64; takes up soluble protein by endocytosis and processes and presents CD4(+) T-cell peptides. Using this aAPC, we were able to determine novel DR-restricted CD4(+) T-cell epitopes and expand long-lived CD4(+) T-cells specific for multiple antigens without growing bystander Foxp3(+) regulatory T cells. Our results suggest that K562-based aAPC may serve as a translatable platform to generate both antigen-specific CD8(+) CTL and CD4(+) T(h).
- Published
- 2010
30. A new TLR2 agonist promotes cross-presentation by mouse and human antigen presenting cells
- Author
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Hidde L. Ploegh, Susanna Aprea, Cecilia Buonsanti, Ugo D'Oro, Michael P. Cooke, Stephanie K. Dougan, Tom Y.-H. Wu, M. Lamine Mbow, Melissa Santone, Ennio De Gregorio, James S Rush, Nicholas Valiante, and Ana M. Avalos
- Subjects
Cytotoxicity, Immunologic ,Ovalbumin ,medicine.medical_treatment ,Immunology ,Antigen-Presenting Cells ,Mice, Transgenic ,CD8-Positive T-Lymphocytes ,Major histocompatibility complex ,Cancer Vaccines ,Immune system ,Cross-Priming ,Antigen ,Adjuvants, Immunologic ,medicine ,Immunology and Allergy ,Cytotoxic T cell ,Animals ,Antigen-presenting cell ,Cell Proliferation ,Pharmacology ,Mice, Inbred BALB C ,biology ,Cross-presentation ,Neoplasms, Experimental ,Molecular biology ,Research Papers ,Toll-Like Receptor 2 ,Mice, Inbred C57BL ,Disease Models, Animal ,Cancer research ,biology.protein ,Cytokines ,Female ,Adjuvant ,CD8 - Abstract
Cross-presentation is the process by which professional APCs load peptides from an extracellularly derived protein onto class I MHC molecules to trigger a CD8(+) T cell response. The ability to enhance this process is therefore relevant for the development of antitumor and antiviral vaccines. We investigated a new TLR2-based adjuvant, Small Molecule Immune Potentiator (SMIP) 2.1, for its ability to stimulate cross-presentation. Using OVA as model antigen, we demonstrated that a SMIP2.1-adjuvanted vaccine formulation induced a greater CD8(+) T cell response, in terms of proliferation, cytokine production and cytolytic activity, than a non-adjuvanted vaccine. Moreover, using an OVA-expressing tumor model, we showed that the CTLs induced by the SMIP2.1 formulated vaccine inhibits tumor growth in vivo. Using a BCR transgenic mouse model we found that B cells could cross-present the OVA antigen when stimulated with SMIP2.1. We also used a flow cytometry assay to detect activation of human CD8(+) T cells isolated from human PBMCs of cytomegalovirus-seropositive donors. Stimulation with SMIP2.1 increased the capacity of human APCs, pulsed in vitro with the pp65 CMV protein, to activate CMV-specific CD8(+) T cells. Therefore, vaccination with an exogenous antigen formulated with SMIP2.1 is a successful strategy for the induction of a cytotoxic T cell response along with antibody production.
- Published
- 2015
31. Modulation of deregulated chaperone-mediated autophagy by a phosphopeptide
- Author
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Jean Paul Briand, Nicolas Page, Sylviane Muller, Christophe Macri, Nicolas Schall, Ana Maria Cuervo, Inmaculada Tasset, Fengjuan Wang, Biotechnologie et signalisation cellulaire (BSC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche de l'Ecole de biotechnologie de Strasbourg (IREBS), Immunopathologie et chimie thérapeutique (ICT), Institut de biologie moléculaire et cellulaire (IBMC), and Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Phosphopeptides ,Mice, Inbred MRL lpr ,LC-MS, liquid chromatography-mass spectrometry ,NBD, nucleotide binding domain ,[SDV.BIO]Life Sciences [q-bio]/Biotechnology ,T-Lymphocytes ,Autoimmunity ,CPZ: chlorpromazine ,SLE, systemic lupus erythematosus ,chemistry.chemical_compound ,Mice ,Chaperone-mediated autophagy ,paraquat, 1, 1′-dimethyl-4, 4′-bipyridyldinium dichloride ,qRT-PCR, quantitative reverse transcriptase-polymerase chain reaction ,immune system diseases ,Serine ,Lupus Erythematosus, Systemic ,antigen-presenting cells ,ALF, artificial lysosomal fluid ,RPL5, ribosomal protein L5 ,Phosphorylation ,skin and connective tissue diseases ,chaperone-mediated autophagy ,HSPA8/HSC70 ,education.field_of_study ,B-Lymphocytes ,SBD, substrate binding domain ,Sciences du Vivant [q-bio]/Biotechnologies ,ELISA, enzyme-linked immunosorbent assay ,MHCII, major histocompatibility complex class II ,class II MHC molecules ,Endocytosis ,Basic Research Paper ,CMA, chaperone-mediated autophagy ,Cell biology ,Lysosomal lumen ,GAPDH, glyceraldehyde-3-phosphate dehydrogenase ,bodipy: BODIPY FL C5 Lactosylceramide/bovine serum albumin ,LAMP2A, lysosomal-associated membrane protein 2A ,RP-HPLC, reversed-phase high-performance liquid chromatography ,autophagy ,CTSD, cathepsin D ,PBS, phosphate-buffered saline ,Endosomes ,Biology ,SEM, standard error of the mean ,Ribosomal protein L5 ,Ribonucleoprotein, U1 Small Nuclear ,lysosomal chaperones ,TFA, trifluoroacetic acid ,Sequestosome 1 ,lysosomes ,CoIP, coimmunoprecipitation ,Downregulation and upregulation ,Animals ,Humans ,education ,Antigen-presenting cell ,Molecular Biology ,SQSTM1/p62, sequestosome 1 ,iv, intravenous ,SNRNP70/U170K: small nuclear ribonucleoprotein 70kDa ,Autophagy ,HSC70 Heat-Shock Proteins ,Histocompatibility Antigens Class II ,Cell Biology ,lupus ,HCQ, hydroxychloroquine ,LC3-II, MAP1LC3-II ,Molecular biology ,Peptide Fragments ,TF, transferrin ,chemistry ,APC, antigen-presenting cell ,Phosphoserine ,heat shock proteins ,NIH 3T3 Cells ,FCS, fetal calf serum ,SD, standard deviation ,DAPI, 4′, 6-diamidino-2-phenylindole ,Molecular Chaperones ,B lymphocytes - Abstract
The P140 peptide, a 21-mer linear peptide (sequence 131-151) generated from the spliceosomal SNRNP70/U1-70K protein, contains a phosphoserine residue at position 140. It significantly ameliorates clinical manifestations in autoimmune patients with systemic lupus erythematosus and enhances survival in MRL/lpr lupus-prone mice. Previous studies showed that after P140 treatment, there is an accumulation of autophagy markers sequestosome 1/p62 and MAP1LC3-II in MRL/lpr B cells, consistent with a downregulation of autophagic flux. We now identify chaperone-mediated autophagy (CMA) as a target of P140 and demonstrate that its inhibitory effect on CMA is likely tied to its ability to alter the composition of HSPA8/HSC70 heterocomplexes. As in the case of HSPA8, expression of the limiting CMA component LAMP2A, which is increased in MRL/lpr B cells, is downregulated after P140 treatment. We also show that P140, but not the unphosphorylated peptide, uses the clathrin-dependent endo-lysosomal pathway to enter into MRL/lpr B lymphocytes and accumulates in the lysosomal lumen where it may directly hamper lysosomal HSPA8 chaperoning functions, and also destabilize LAMP2A in lysosomes as a result of its effect on HSP90AA1. This dual effect may interfere with the endogenous autoantigen processing and loading to major histocompatibility complex class II molecules and as a consequence, lead to lower activation of autoreactive T cells. These results shed light on mechanisms by which P140 can modulate lupus disease and exert its tolerogenic activity in patients. The unique selective inhibitory effect of the P140 peptide on CMA may be harnessed in other pathological conditions in which reduction of CMA activity would be desired.
- Published
- 2015
32. Breaking the co-operation between bystander T-cells and natural killer cells prevents the development of immunosuppression after traumatic skeletal muscle injury in mice
- Author
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Florian Wirsdörfer, Stefanie B. Flohé, Wiebke Hansen, Jörg M. Bangen, and Eva Pastille
- Subjects
Male ,Adoptive cell transfer ,Medizin ,DAMP, damage-associated molecular pattern ,Priming (immunology) ,Immune tolerance ,BMDC, bone marrow–derived dendritic cell ,GM1, ganglioside monosialic acid ,DC, dendritic cell ,Interferon ,s.c., subcutaneously ,Interferon gamma ,pLN, popliteal lymph node ,Cells, Cultured ,Mice, Knockout ,Mice, Inbred BALB C ,immunosuppression ,natural killer cells ,FoxP3, transcription factor forkhead box P3 ,Cell Differentiation ,General Medicine ,CFSE, carboxyfluorescein succinimidyl ester ,Acquired immune system ,Flow Cytometry ,Killer Cells, Natural ,HSP, heat shock protein ,Th1, Th type 1 ,TLRs, toll-like receptors ,NK, natural killer ,PAMP, pathogen-associated molecular pattern ,medicine.drug ,wt, wild-type ,Ovalbumin ,injury ,aa, amino acid ,CD, cluster of differentiation ,Antigen-Presenting Cells ,Interferon-gamma ,OVA, ovalbumin ,Intensive care ,i.v., intravenous ,MyD88, myeloid differentiation factor 88 ,medicine ,Immune Tolerance ,Animals ,MHC, major histocompatibility complex ,IFN, interferon ,RAG, recombination-activating gene ,Antigen-presenting cell ,Muscle, Skeletal ,Th, T helper ,Original Paper ,business.industry ,myeloid differentiation factor 88 (MyD88) ,Bystander Effect ,Th1 Cells ,cytokines ,regulatory T-cells ,HMGB1, high mobility group box 1 ,IL, interleukin ,Toll-Like Receptor 4 ,Tregs, regulatory T-cells ,APC, antigen-presenting cell ,Immunology ,Myeloid Differentiation Factor 88 ,pOVA, OVA peptide ,Lymph Nodes ,FCS, fetal calf serum ,business - Abstract
Nosocomial infections represent serious complications after traumatic or surgical injuries in intensive care units. The pathogenesis of the underlying immunosuppression is only incompletely understood. In the present study, we investigated whether injury interferes with the function of the adaptive immune system in particular with the differentiation of antigen-specific T helper (Th)-cell responses in vivo. We used a mouse model for traumatic gastrocnemius muscle injury. Ovalbumin (OVA), which served as a foreign model antigen, was injected into the hind footpads for determination of the differentiation of OVA-specific Th-cells in the draining popliteal lymph node (pLN). The release of interferon (IFN)-γ from OVA-specific Th-cells was impaired within 24 h after injury and this impairment persisted for at least 7 days. In contrast, the proliferation of OVA-specific Th-cells remained unaffected. Injury did not modulate the function of antigen-presenting cells (APCs) in the pLN. Adoptive transfer of total T-cells from pLNs of injured mice inhibited IFN-γ production by OVA-specific Th-cells in naive mice. Suppressed Th1 priming did not occur in lymphocyte-deficient mice after injury but was restored by administration of T-cells before injury. Moreover, the suppression of Th1 differentiation required the presence of natural killer (NK) cells that were recruited to the pLN after injury; this recruitment was dependent on lymphocytes, toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88). In summary, upon traumatic skeletal muscle injury T-cells and NK cells together prevent the development of protective Th1 immunity. Breaking this co-operation might be a novel approach to reduce the risk of infectious complications after injury., After traumatic skeletal muscle injury, natural killer (NK) cells are recruited to the draining lymph node in a TLR4 (toll-like receptor 4)–myeloid differentiation factor 88 (MyD88)-dependent manner and impair the development of specific T-cell responses. The suppressed T-cell function might increase the susceptibility of severely injured patients to nosocomial infections.
- Published
- 2015
33. SYK regulates macrophage MHC-II expression via activation of autophagy in response to oxidized LDL
- Author
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Ayelet Gonen, Yury I. Miller, Soo-Ho Choi, Felicidad Almazan, Joseph L. Witztum, Cody J. Diehl, and Jungsu Kim
- Subjects
green fluorescent protein ,receptor ,toll-like receptor 4 ,low affinity ,Lymphocyte Activation ,Cardiovascular ,Mice ,Epitopes ,spleen tyrosine kinase ,Fc fragment of IgG ,antigen-presenting cells ,SYK ,oxidation-specific antibodies ,Aetiology ,PBS ,diphenyleneiodonium ,major histocompatibility complex class II ,reactive oxygen species ,Membrane Glycoproteins ,malondialdehyde-acetaldehyde modified low density lipoprotein ,Intracellular Signaling Peptides and Proteins ,ROS ,NOX ,Acquired immune system ,piceatannol ,Up-Regulation ,Lipoproteins, LDL ,high-fat diet ,malondialdehyde modified low density lipoprotein ,TCR ,Biochemistry & Molecular Biology ,IgM ,FCGR ,IgG ,Lipoproteins ,1.1 Normal biological development and functioning ,Hypercholesterolemia ,LDL ,Antigen ,NAPDH oxidase ,bafilomycin A1 ,Baf ,MHC-II ,OSE ,Molecular Biology ,MAP1LC3/LC3 ,microtubule-associated protein 1 light chain 3 ,B cell receptor ,Macrophages ,Inflammatory and immune system ,Histocompatibility Antigens Class II ,NADPH Oxidases ,MAPK ,Mice, Inbred C57BL ,HFD ,oxidized low density lipoprotein ,3MA ,Biochemistry and Cell Biology ,T cell receptor ,Reactive Oxygen Species ,CD4-Positive T-Lymphocytes ,mitogen-activated protein kinase ,TNF ,minimally modified low density lipoprotein ,Syk ,Inbred C57BL ,immunoglobulin G ,ITAM ,immunoglobulin M ,2.1 Biological and endogenous factors ,oxidation specific epitopes ,TLR4 ,biology ,lipopolysaccharide ,Protein-Tyrosine Kinases ,BCR ,bone marrow-derived macrophage ,Basic Research Paper ,DPI ,Proto-Oncogene Proteins c-bcl-2 ,NADPH Oxidase 2 ,lipids (amino acids, peptides, and proteins) ,Oxidation-Reduction ,OxLDL ,autophagy ,LPS ,tumor necrosis factor ,Antigen presentation ,chemical and pharmacologic phenomena ,phosphate-buffered saline ,Major histocompatibility complex ,GFP ,interleukin 2 ,Immune system ,Underpinning research ,Autophagy ,Animals ,Syk Kinase ,Mitogen-Activated Protein Kinase 8 ,IL2 ,PIC ,3-methyladenine ,Cell Biology ,mmLDL ,BMDM ,Atherosclerosis ,MAA-LDL ,MDA-LDL ,Ether-A-Go-Go Potassium Channels ,immunoreceptor tyrosine-based activation motif ,RAW 264.7 Cells ,Immunoglobulin G ,LDL receptor ,biology.protein ,Cancer research ,APCs - Abstract
Adaptive immunity, which plays an important role in the development of atherosclerosis, is mediated by major histocompatibility complex (MHC)-dependent antigen presentation. In atherosclerotic lesions, macrophages constitute an important class of antigen-presenting cells that activate adaptive immune responses to oxidized low-density lipoprotein (OxLDL). It has been reported that autophagy regulates adaptive immune responses by enhancing antigen presentation to MHC class II (MHC-II). In a previous study, we have demonstrated that SYK (spleen tyrosine kinase) regulates generation of reactive oxygen species (ROS) and activation of MAPK8/JNK1 in macrophages. Because ROS and MAPK8 are known to regulate autophagy, in this study we investigated the role of SYK in autophagy, MHC-II expression and adaptive immune response to OxLDL. We demonstrate that OxLDL induces autophagosome formation, MHC-II expression, and phosphorylation of SYK in macrophages. Gene knockout and pharmacological inhibitors of NOX2 and MAPK8 reduced OxLDL-induced autophagy. Using bone marrow-derived macrophages isolated from wild-type and myeloid-specific SYK knockout mice, we demonstrate that SYK regulates OxLDL-induced ROS generation, MAPK8 activation, BECN1-BCL2 dissociation, autophagosome formation and presentation of OxLDL-derived antigens to CD4+ T cells. ldlr−/−syk−/− mice fed a high-fat diet produced lower levels of IgG to malondialdehyde (MDA)-LDL, malondialdehyde-acetaldehyde (MAA)-LDL, and OxLDL compared to ldlr−/− mice. These results provide new insights into the mechanisms by which SYK regulates MHC-II expression via autophagy in macrophages and may contribute to regulation of adaptive immune responses in atherosclerosis.
- Published
- 2015
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34. Protection against Experimental Autoimmune Myocarditis Is Mediated by Interleukin-10-Producing T Cells that Are Controlled by Dendritic Cells
- Author
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Janet S. Heuser, Ya Li, Stanley D. Kosanke, Madeleine W. Cunningham, and Mark E. Hemric
- Subjects
Adoptive cell transfer ,T-Lymphocytes ,medicine.medical_treatment ,Antigen-Presenting Cells ,Epitope ,Autoimmune Diseases ,Pathology and Forensic Medicine ,Interferon-gamma ,Animals ,Medicine ,Antigen-presenting cell ,Cell Proliferation ,Immunomagnetic Separation ,Reverse Transcriptase Polymerase Chain Reaction ,business.industry ,Interleukin ,Dendritic Cells ,Dendritic cell ,T lymphocyte ,Flow Cytometry ,Adoptive Transfer ,Interleukin-12 ,Interleukin-10 ,Rats ,Cell biology ,Original Research Paper ,Myocarditis ,Interleukin 10 ,Cytokine ,Rats, Inbred Lew ,Immunology ,Female ,business ,Cardiac Myosins - Abstract
Experimental autoimmune myocarditis (EAM) can be induced in the Lewis rat by cardiac myosin or its cryptic S2-16 peptide epitope (amino acids 1052 to 1076). To investigate cellular mechanisms and the role of antigen-presenting cells in regulation of myocarditis, we induced protection against EAM in Lewis rats by administration of S2-16 peptide in incomplete Freund's adjuvant (IFA). Protection to EAM was associated with activation of S2-16-reactive splenocytes secreting high levels of interleukin (IL)-10 and reduced levels of interferon-gamma and IL-2. Adoptive transfer of S2-16:IFA-induced splenocytes producing IL-10 suppressed myocarditis induction in syngeneic recipients, suggesting their regulatory cell nature. However, exposure of S2-16:IFA-induced cells to inflammatory cytokine IL-12 converted them to Th1 effectors that transferred EAM. Differentiated function of S2-16-reactive T cells in protected rats resulted from increased IL-10 production by dendritic cells (DCs). Purified DCs from S2-16:IFA-treated rats promoted S2-16-reactive CD4+ T cells to produce increased IL-10 and reduced interferon-gamma. In addition, adoptive transfer of IL-10-producing DCs from S2-16:IFA-treated rats also induced protection to EAM in recipient rats. These studies demonstrated DCs and key cytokines, such as IL-10 and IL-12, regulated the fate of T cells in myocarditis development in the Lewis rat.
- Published
- 2005
35. Preparation of Bead-supported Lipid Bilayers to Study the Particulate Output of T Cell Immune Synapses.
- Author
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Céspedes PF and Dustin ML
- Subjects
- Lymphocyte Activation, Synapses, T-Lymphocytes, Cytotoxic, T-Lymphocytes, Helper-Inducer, Antigen-Presenting Cells, Lipid Bilayers metabolism
- Abstract
Antigen-presenting cells (APCs) present three activating signals to T cells engaged in physical contact: 1) antigen, 2) costimulation/corepression, and 3) soluble cytokines. T cells release two kinds of effector particles in response to activation: trans-synaptic vesicles (tSVs) and supramolecular attack particles, which transfer intercellular messengers and mediate cytotoxicity, respectively. These entities are quickly internalized by APCs engaged in physical contact with T cells, making their characterization daunting. This paper presents the protocol to fabricate and use Bead-Supported Lipid Bilayers (BSLBs) as antigen-presenting cell (APC) mimetics to capture and analyze these trans-synaptic particles. Also described are the protocols for the absolute measurements of protein densities on cell surfaces, the reconstitution of BSLBs with such physiological levels, and the flow cytometry procedure for tracking synaptic particle release by T cells. This protocol can be adapted to study the effects of individual proteins, complex ligand mixtures, pathogen virulence determinants, and drugs on the effector output of T cells, including helper T cells, cytotoxic T lymphocytes, regulatory T cells, and chimeric antigen receptor-expressing T cells (CART).
- Published
- 2022
- Full Text
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36. Cellular target of UVB-induced DNA damage resulting in local suppression of contact hypersensitivity
- Author
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Margaret L. Kripke, Jean Krutmann, Vijay Shreedhar, Arie A. Vink, and Len Roza
- Subjects
Ultraviolet Rays ,DNA damage ,Cell ,Antigen-presenting cells ,Biophysics ,Biology ,Dermatitis, Contact ,ultraviolet b radiation ,immunology ,chemistry.chemical_compound ,medicine ,Photoimmunology ,Animals ,Humans ,Radiology, Nuclear Medicine and imaging ,Antigen-presenting cell ,conference paper ,Cells, Cultured ,Immunosuppression Therapy ,Radiation ,Models, Genetic ,Radiological and Ultrasound Technology ,Models, Immunological ,Contact hypersensitivity ,DNA ,medicine.disease ,Cell biology ,Ultraviolet B radiation ,medicine.anatomical_structure ,priority journal ,chemistry ,Contact allergy ,antigen presenting cell ,Immunology ,contact allergy ,UVB ,Contact dermatitis ,Immunosuppression ,DNA Damage - Abstract
Experimental data are reviewed that lend support to the hypothesis that formation of DNA damage is the initiation event of local suppression of contact hypersensitivity (CHS) after exposure to ultraviolet (UV) radiaton and that the antigen-presenting cell (APC) is an important traget for this DNA damage. Chemicals/CAS: DNA, 9007-49-2
- Published
- 1998
37. Amelioration of renal ischaemia-reperfusion injury by liposomal delivery of curcumin to renal tubular epithelial and antigen-presenting cells
- Author
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N M, Rogers, M D, Stephenson, A R, Kitching, J D, Horowitz, and P T H, Coates
- Subjects
Male ,Curcumin ,Time Factors ,Reverse Transcriptase Polymerase Chain Reaction ,Anti-Inflammatory Agents, Non-Steroidal ,Blotting, Western ,NF-kappa B ,Antigen-Presenting Cells ,Epithelial Cells ,Research Papers ,Antioxidants ,Mice, Inbred C57BL ,Mice ,Oxidative Stress ,Drug Delivery Systems ,Kidney Tubules ,Reperfusion Injury ,Liposomes ,In Situ Nick-End Labeling ,Animals ,Cytokines ,Chemokines - Abstract
Renal ischaemia-reperfusion (IR) injury is an inevitable consequence of renal transplantation, causing significant graft injury, increasing the risk of rejection and contributing to poor long-term graft outcome. Renal injury is mediated by cytokine and chemokine synthesis, inflammation and oxidative stress resulting from activation of the NF-κB pathway.We utilized liposomal incorporation of a potent inhibitor of the NF-κB pathway, curcumin, to target delivery to renal tubular epithelial and antigen-presenting cells. Liposomes containing curcumin were administered before bilateral renal ischaemia in C57/B6 mice, with subsequent reperfusion. Renal function was assessed from plasma levels of urea and creatinine, 4 and 24 h after reperfusion. Renal tissue was examined for NF-κB activity and oxidative stress (histology, immunostaining) and for apoptosis (TUNEL). Cytokines and chemokines were measured by RT-PCR and Western blotting.Liposomal curcumin significantly improved serum creatinine, reduced histological injury and cellular apoptosis and lowered Toll-like receptor-4, heat shock protein-70 and TNF-α mRNA expression. Liposomal curcumin also reduced neutrophil infiltration and diminished inflammatory chemokine expression. Curcumin liposomes reduced intracellular superoxide generation and increased superoxide dismutase levels, decreased inducible NOS mRNA expression and 3-nitrotyrosine staining consistent with limitations in nitrosative stress and inhibited renal tubular mRNA and protein expression of thioredoxin-interacting protein. These actions of curcumin were mediated by inhibition of NF-κB, MAPK and phospho-S6 ribosomal protein.Liposomal delivery of curcumin promoted effective, targeted delivery of this non-toxic compound that provided cytoprotection via anti-inflammatory and multiple antioxidant mechanisms following renal IR injury.
- Published
- 2011
38. CD277 is a negative co-stimulatory molecule universally expressed by ovarian cancer microenvironmental cells
- Author
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Yolanda Nesbeth, Jose R. Conejo-Garcia, Diana Martinez, Uciane K. Scarlett, Juan R. Cubillos-Ruiz, Melanie R. Rutkowski, and Ana L. Camposeco-Jacobs
- Subjects
Models, Molecular ,Myeloid ,Protein Conformation ,medicine.medical_treatment ,T-Lymphocytes ,CASP8 and FADD-Like Apoptosis Regulating Protein ,Lymphocyte Activation ,0302 clinical medicine ,Tumor Microenvironment ,tumor immunology ,Ovarian Neoplasms ,0303 health sciences ,Membrane Glycoproteins ,Research Papers ,Cell Hypoxia ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Cytokines ,Female ,immunotherapy ,Inflammation Mediators ,Stromal cell ,butyrophilin ,dendritic cell ,Molecular Sequence Data ,Antigen-Presenting Cells ,Biology ,Transfection ,03 medical and health sciences ,Structure-Activity Relationship ,Immune system ,Antigens, CD ,medicine ,Humans ,Amino Acid Sequence ,Antigen-presenting cell ,030304 developmental biology ,Cell Proliferation ,immune evasion ,Tumor microenvironment ,Butyrophilins ,Macrophages ,Dendritic cell ,Immunotherapy ,Dendritic Cells ,medicine.disease ,Coculture Techniques ,Immunology ,Stromal Cells ,Ovarian cancer ,K562 Cells - Abstract
Received: August 7, 2010 , Accepted: August 25, 2010 , Published: September 11, 2010 // CD277, a member of the butyrophilin subfamily 3 (BTN3), shares significant sequence similarities and predicted common structural features with inhibitory B7-H4 and other members of the B7 superfamily. Here we report that CD277 is consistently expressed in stromal, as well as tumor cells in the microenvironment of human advanced ovarian carcinoma specimens, both of primary and metastatic origin. MHC-II+ myeloid antigenpresenting leukocytes (dendritic cells and macrophages) express significantly higher levels of surface CD277, compared to other tumor-infiltrating leukocyte subsets, and this expression is significantly up-regulated by multiple common tumor microenvironmental signals, including VEGF and CCL3. Most importantly, engagement of CD277 on the surface of TCR-stimulated T cells inhibits their otherwise robust expansion and production of Th1 cytokines by preventing the up-regulation of cFLIP. Our results point to a role for CD277 up-regulated by microenvironmental signals in the acquisition of a regulatory phenotype by tumor-associated myeloid cells. Consequently, CD277, and likely other butyrophilins and butyrophilin-like molecules, emerge as regular players in the orchestration of immunosuppressive networks in ovarian cancer, and therefore new targets for interventions to overcome immune evasion and boost anti-tumor immunity in cancer patients.
- Published
- 2010
39. The Role of Antigenic Drive and Tumor-Infiltrating Accessory Cells in the Pathogenesis of Helicobacter-Induced Mucosa-Associated Lymphoid Tissue Lymphoma
- Author
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Pauline Chu, Michael F. Dixon, Jani O'Rourke, Anne Mueller, Amanda Chu, Donna M. Bouley, Stanley Falkow, and Adrian Lee
- Subjects
CD4-Positive T-Lymphocytes ,Pathology ,medicine.medical_specialty ,Lymphoid Tissue ,Antigen-Presenting Cells ,Severity of Illness Index ,Pathology and Forensic Medicine ,Helicobacter Infections ,Mice ,Immunophenotyping ,Th2 Cells ,Recurrence ,medicine ,Animals ,Helicobacter ,Antigens ,Antigen-presenting cell ,Mice, Inbred BALB C ,biology ,Follicular dendritic cells ,Remission Induction ,MALT lymphoma ,Dendritic Cells ,Lymphoma, B-Cell, Marginal Zone ,biology.organism_classification ,medicine.disease ,Lymphoma ,Anti-Bacterial Agents ,Original Research Paper ,Lymphatic system ,Multigene Family ,Helicobacter felis ,Drug Therapy, Combination ,Female ,Neoplasm Recurrence, Local - Abstract
Gastric B-cell lymphoma of mucosa-associated lymphoid tissue type is closely linked to chronic Helicobacter pylori infection. Most clinical and histopathological features of the tumor can be reproduced by prolonged Helicobacter infection of BALB/c mice. In this study, we have addressed the role of antigenic stimulation in the pathogenesis of the lymphoma by experimental infection with Helicobacter felis, followed by antibiotic eradication therapy and subsequent re-infection. Antimicrobial therapy was successful in 75% of mice and led to complete histological but not "molecular" tumor remission. Although lympho-epithelial lesions disappeared and most gastric lymphoid aggregates resolved, transcriptional profiling revealed the long-term mucosal persistence of residual B cells. Experimental re-introduction of Helicobacter led to very rapid recurrence of the lymphomas, which differed from the original lesions by higher proliferative indices and more aggressive behavior. Immunophenotyping of tumor cells revealed massive infiltration of lesions by CD4(+) T cells, which express CD 28, CD 69, and interleukin-4 but not interferon-gamma, suggesting that tumor B-cell proliferation was driven by Th 2-polarized, immunocompetent, and activated T cells. Tumors were also densely colonized by follicular dendritic cells, whose numbers were closely associated with and predictive of treatment outcome.
- Published
- 2005
40. Astragalus-mediated stimulation on antigen-presenting cells could result in higher IL-21 production from CXCR5 + Tfh-like cells and better IL-21-mediated effector functions.
- Author
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Dong Q, Pu J, Du T, Xu S, Liu W, Liu L, Wang Z, and Cai C
- Subjects
- Adult, Astragalus propinquus immunology, Carcinoma, Renal Cell immunology, Drugs, Chinese Herbal, Female, Gene Expression Regulation, Neoplastic, Humans, Immunity, Humoral, Kidney Neoplasms immunology, Male, Medicine, Chinese Traditional, Middle Aged, Antigen-Presenting Cells immunology, CD8-Positive T-Lymphocytes immunology, Carcinoma, Renal Cell therapy, Germinal Center immunology, Interleukins metabolism, Kidney Neoplasms therapy, Receptors, CXCR5 metabolism, T-Lymphocytes, Helper-Inducer immunology
- Abstract
T cells in renal cell carcinoma (RCC) patients display multiple features of impairment and exhaustion. Here, we hypothesize that Astragalus membranaceus, a herbal medicine commonly used to accompany chemotherapy, might have adjuvating effects on T cells from RCC patients. To investigate this, circulating T cells from healthy individuals and RCC patients were cocultured ex vivo with aqueous extract from Astragalus. Functional characteristics of T cells in the absence and presence of Astragalus extract were then compared. We first identified a downregulation of IL-21 expression in RCC patients in association with a functional dysregulation of CXCR5
+ Tfh-like cells. Astragalus extract could significantly increase IL-21 expression in a dose-dependent manner. This Astragalus-mediated effect depended on the presence of antigen-presenting cells (APCs), as purified CXCR5+ Tfh-like cells presented little IL-21 upregulation following Astragalus stimulation. APCs primed by Astragalus extract also promoted IL-21 expression from Tfh-like cells. Interestingly, Astragalus-stimulated Tfh-like cells presented enhanced helper function and resulted in higher humoral responses and better CD8 T cell survival. This effect was dependent on the presence of IL-21. Overall, these data indicated that Astragalus could enhance IL-21 production and effector function from CXCR5+ Tfh-like cells in a manner that depended on the presence of APCs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)- Published
- 2021
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41. Risk-period-cohort approach for averting identification problems in longitudinal models.
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Gunzler, Douglas D., Perzynski, Adam T., Dawson, Neal V., Kauffman, Kelley, Liu, Jintao, and Dalton, Jarrod E.
- Subjects
AGE ,LONGITUDINAL method ,GERONTOLOGY ,CYTOLOGY ,MONTE Carlo method - Abstract
In epidemiology, gerontology, human development and the social sciences, age-period-cohort (APC) models are used to study the variability in trajectories of change over time. A well-known issue exists in simultaneously identifying age, period and birth cohort effects, namely that the three characteristics comprise a perfectly collinear system. That is, since age = period−cohort, only two of these effects are estimable at a time. In this paper, we introduce an alternative framework for considering effects relating to age, period and birth cohort. In particular, instead of directly modeling age in the presence of period and cohort effects, we propose a risk modeling approach to characterize age-related risk (i.e., a hybrid of multiple biological and sociological influences to evaluate phenomena associated with growing older). The properties of this approach, termed risk-period-cohort (RPC), are described in this paper and studied by simulations. We show that, except for pathological circumstances where risk is uniquely determined by age, using such risk indices obviates the problem of collinearity. We also show that the size of the chronological age effect in the risk prediction model associates with the correlation between a risk index and chronological age and that the RPC approach can satisfactorily recover cohort and period effects in most cases. We illustrate the advantages of RPC compared to traditional APC analysis on 27496 individuals from NHANES survey data (2005–2016) to study the longitudinal variability in depression screening over time. Our RPC method has broad implications for examining processes of change over time in longitudinal studies. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
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42. Cellular target of UVB-induced DNA damage resulting in local suppression of contact hypersensitivity
- Subjects
Cultured ,Ultraviolet Rays ,Cells ,Antigen-presenting cells ,Dermatitis ,DNA ,Contact hypersensitivity ,ultraviolet b radiation ,immunology ,Immunological ,priority journal ,Genetic ,Models ,antigen presenting cell ,Contact ,contact allergy ,DNA damage ,Photoimmunology ,Animals ,Humans ,UVB ,Biology ,Immunosuppression ,conference paper - Abstract
Experimental data are reviewed that lend support to the hypothesis that formation of DNA damage is the initiation event of local suppression of contact hypersensitivity (CHS) after exposure to ultraviolet (UV) radiaton and that the antigen-presenting cell (APC) is an important traget for this DNA damage. Chemicals/CAS: DNA, 9007-49-2
- Published
- 1998
43. New immunoenzyme-cytochemical stainings for the in situ detection of epitope specificity and isotype of antibody forming B cells in experimental and natural (auto)immune responses in animals and man
- Author
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Claassen, E., Gerritse, K., Laman, J.D., Boersma, W.J.A., and Medisch Biologisch Laboratorium TNO
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Antibody producing cell ,T-Lymphocytes ,Antigen-Presenting Cells ,Autoimmunity ,In situ ,Horseradish peroxidase ,Epitopes ,Antibody Specificity ,Alkaline phosphatase ,Animalia ,Antibody ,Priority journal ,B cell ,B-Lymphocytes ,Conference paper ,Beta galactosidase ,B lymphocyte ,Staining and Labeling ,Animal ,Macrophages ,Armoracia rusticana ,Immunohistochemistry ,Immunoglobulin Isotypes ,Enzyme ,Rabbits ,Immunocytochemistry ,Spleen ,Human - Published
- 1992
44. New immunoenzyme-cytochemical stainings for the in situ detection of epitope specificity and isotype of antibody forming B cells in experimental and natural (auto)immune responses in animals and man
- Subjects
Antibody producing cell ,T-Lymphocytes ,Antigen-Presenting Cells ,Autoimmunity ,In situ ,Horseradish peroxidase ,Epitopes ,Antibody Specificity ,Alkaline phosphatase ,Animalia ,Antibody ,Priority journal ,B cell ,B-Lymphocytes ,Conference paper ,Beta galactosidase ,B lymphocyte ,Staining and Labeling ,Animal ,Macrophages ,Armoracia rusticana ,Immunohistochemistry ,Immunoglobulin Isotypes ,Enzyme ,Rabbits ,Immunocytochemistry ,Spleen ,Human - Published
- 1992
45. Borna disease virus-infected astrocytes function in vitro as antigen-presenting and target cells for virus-specific CD4-bearing lymphocytes
- Author
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Jürgen A. Richt and L. Stitz
- Subjects
CD4-Positive T-Lymphocytes ,Cytotoxicity, Immunologic ,T cell ,viruses ,Antigen presentation ,Antigen-Presenting Cells ,Biology ,Lymphocyte Activation ,Antigen ,Interferon ,Virology ,medicine ,Cytotoxic T cell ,Animals ,Antigen-presenting cell ,Borna disease virus ,Antigens, Viral ,Cells, Cultured ,Gamma Interferon ,Borna disease ,MHC class II ,Release Assay ,Histocompatibility Antigens Class II ,Antibodies, Monoclonal ,Brain ,Myelin Basic Protein ,General Medicine ,Original Papers ,Rats ,medicine.anatomical_structure ,Animals, Newborn ,Borna Disease ,Rats, Inbred Lew ,Astrocytes ,biology.protein ,Target Cell ,medicine.drug ,T-Lymphocytes, Cytotoxic - Abstract
Summary Astrocytes isolated from the brain of newborn Lewis rats and an astrocytic cell line were susceptible to infection with the neurotropic Borna disease virus in vitro. Since astrocytes also have been found to be infected in vivo it seemed appropriate to test this cell type for interaction with a Borna disease virus-specific CD4+ T cell line. Borna disease virus-infected astrocytes were found to be capable of presenting virus-specific antigen to virus-specific T cells in vitro. However, the response was significantly enhanced if the purified 38/39 kDa Borna disease virus-specific protein was added exogenously to the cultures. Beside the function as antigen-presenting cells for various antigens including virus-specific protein and myelin basic protein, persistently infected astrocytes were also found to act as target cells for a CD4+ T cell line as shown in conventional51Cr release assays after induction of MHC class II expression by gamma interferon. Infection of astrocytes alone did not cause expression of this self antigen. It could be shown that the ability of CD4+ BDV-specific T cells to mediate lysis was in part dependent on the stage of activation. Lymphocytes “activated” before testing exerted high lysis after only 4h of coincubation with target cells, whereas “resting” T cells did not cause significant lysis until 12h of coincubation. The dependence of the interaction between effector and target cells on MHC class II antigen was demonstrated by the finding that antibodies to Ia antigens reduced lysis of target cells.
- Published
- 1992
46. Research from CHA University Yields New Study Findings on Immunotherapy (Dendritic Cell-Based Immunotherapy: The Importance of Dendritic Cell Migration).
- Subjects
DENDRITIC cells ,CELL migration ,IMMUNOTHERAPY ,RETICULO-endothelial system ,ALZHEIMER'S disease - Abstract
Researchers from CHA University in South Korea have conducted a study on dendritic cell-based immunotherapy and the importance of dendritic cell migration. Dendritic cells are specialized antigen-presenting cells that play a crucial role in maintaining self-tolerance and initiating immune responses. However, there are challenges in using dendritic cell-based immunotherapy, such as limited availability, immune escape in tumors, and the need for effective combination therapies. The researchers suggest that increasing the population of migratory dendritic cells could enhance the effectiveness of immunotherapy. This paper provides an overview of the importance of dendritic cell migration and current research progress in the field. [Extracted from the article]
- Published
- 2024
47. Genetic polymorphisms of proteasome subunit genes of the MHC-I antigen-presenting system are associated with cervical cancer in a Chinese Han population.
- Author
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Li C, Dai S, Yan Z, Zhang X, Liu S, Wang X, Wang J, Shi L, and Yao Y
- Subjects
- Adult, Case-Control Studies, Female, Gene Frequency genetics, Genotype, Humans, Middle Aged, Uterine Cervical Dysplasia genetics, Antigen-Presenting Cells immunology, Asian People genetics, Genetic Predisposition to Disease genetics, Histocompatibility Antigens Class I genetics, Polymorphism, Single Nucleotide genetics, Proteasome Endopeptidase Complex genetics, Uterine Cervical Neoplasms genetics
- Abstract
Proteasome subunit beta types 8 and 9 (PSMB8, PSMB9) play critical roles in the human leukocyte antigen class I (HLA I)-presenting system. Studies have suggested that polymorphisms in the PSMB8 and PSMB9 genes may influence the immune functions of PSMB8 and PSMB9, and thus be associated with various human cancers. We investigated associations involving single nucleotide polymorphisms (SNPs) rs2071543 in PSMB8, rs1351383, rs17587 and rs2127675 in PSMB9 and risk of cervical intraepithelial neoplasia (CIN) and cervical cancer in a Chinese Han population. A total of 543 patients with CIN, 1008 patients with cervical cancer, and 1120 healthy individuals were enrolled. Agena MassArray was used for SNP genotyping of PSMB8 and PSMB9. Associations involving these SNPs and risk of CIN and cervical cancer were analysed. Our results showed that the PSMB8 T/T and T/G genotypes of rs2071543 may be associated with a higher risk of CIN (P = 0.011, OR = 1.35,95% CI: 1.07-1.70) and cervical cancer (P = 0.006, OR = 1.31, 95% CI: 1.08-1.59). For rs17587, the A allele (P = 0.001, OR = 1.303, 95% CI: 1.115-1.522), and the A/A and A/G genotypes (P = 0.001, OR = 1.36, 95% CI: 1.13-1.63) may be risk factors for cervical cancer. These results indicated that PSMB8 rs2071543 might influence susceptibility to CIN and cervical cancer, and PSMB9 rs17587 might influence cervical cancer susceptibility in a Chinese Han population., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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48. α7 nAChRs expressed on antigen presenting cells are insensitive to the conventional antagonists α-bungarotoxin and methyllycaconitine.
- Author
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Mashimo M, Takeshima S, Okuyama H, Matsurida A, Murase M, Ono S, Kawashima K, and Fujii T
- Subjects
- Aconitine pharmacology, Animals, Antigen Presentation drug effects, Benzylidene Compounds pharmacology, Calcium Signaling drug effects, Cell Differentiation drug effects, Cells, Cultured, Cytokines metabolism, Lymphocyte Activation, Mice, Mice, Inbred BALB C, Mice, Transgenic, Pyridines pharmacology, alpha7 Nicotinic Acetylcholine Receptor genetics, Aconitine analogs & derivatives, Antigen-Presenting Cells immunology, Bungarotoxins pharmacology, CD4-Positive T-Lymphocytes immunology, T-Lymphocytes, Regulatory immunology, alpha7 Nicotinic Acetylcholine Receptor metabolism
- Abstract
Expression of α7 nicotinic acetylcholine receptors (nAChRs) on antigen presenting cells (APCs), such as macrophages and dendritic cells, is now well established. We have shown that GTS-21, a selective α7 nAChR agonist, downregulates APC-dependent CD4
+ T cell differentiation into regulatory T cells (Tregs) and effector Th1, Th2 and Th17 cells by inhibiting antigen processing, thereby interfering with antigen presentation. α7 nAChRs on Jurkat human leukemic T cells require functional T cell receptors (TCRs)/CD3 and leukocyte-specific tyrosine kinase to mediate nicotine-induced Ca2+ -signaling via Ca2+ release from intracellular stores, and are insensitive to two conventional α7 nAChR antagonists, α-bungarotoxin (α-BTX) and methyllycaconitine (MLA). We investigated the effects of GTS-21, α-BTX and MLA on ovalbumin (OVA)-induced Th cytokine release from spleen cells isolated from OVA-specific TCR transgenic DO11.10 mice. We found that: (1) GTS-21 dose-dependently suppresses OVA-induced IFN-γ, IL-4 and IL-17 release, but neither α-BTX nor MLA alone affected the OVA-induced cytokine release. (2) Neither α-BTX nor MLA abolished the suppressive effects of GTS-21 on IFN-γ and IL-17 release from OVA-activated DO11.10 spleen cells. (3) GTS-21 significantly suppressed OVA-induced APC-dependent CD4+ T cell differentiation into Tregs. Neither MLA nor mecamylamine, a non-specific nAChR antagonist, abolished the suppressive effect of GTS-21 on Treg differentiation. These results suggest that α7 nAChRs on APCs involved in cytokine synthesis and T cell differentiation are insensitive to the conventional α7 nAChR antagonists, α-BTX and MLA, and that α7 nAChRs on APCs differ pharmacologically from those in neurons., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)- Published
- 2020
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49. The epigenetic face of lupus: Focus on antigen-presenting cells.
- Author
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Wardowska A
- Subjects
- Animals, DNA Methylation, Epigenesis, Genetic, Histones metabolism, Humans, Lymphocyte Activation, RNA, Untranslated genetics, Antigen-Presenting Cells immunology, B-Lymphocytes immunology, Dendritic Cells immunology, Lupus Erythematosus, Systemic immunology, T-Lymphocytes immunology
- Abstract
In recent years, epigenetic mechanisms became widely known due to their ability to regulate and maintain physiological processes such as cell growth, development, differentiation and genomic stability. When dysregulated, epigenetic mechanisms, may introduce gene expression changes and disturbance in immune homeostasis leading to autoimmune diseases. Systemic lupus erythematosus (SLE), the most extensively studied autoimmune disorder, has already been correlated with epigenetic modifications, especially in T cells. Since these cell rely on antigen presentation, it may be assumed that erroneous activity of antigen-presenting cells (APCs), culminates in T cell abnormalities. In this review we summarize and discuss the epigenetic modifications in SLE affected APCs, with the focus on dendritic cells (DCs), B cells and monocytes. Unravelling this aspect of SLE pathogenesis, might result in identification of new disease biomarkers and putative therapeutic approaches., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Author. Published by Elsevier B.V. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
50. Diminished mitogen-induced T cell proliferation by Trypanosoma cruzi antigens associated with antigen-presenting cell modulation and CD3 signaling.
- Author
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Gómez-Olarte S, Bolaños NI, Cuéllar A, Puerta CJ, and González JM
- Subjects
- Adult, Cell Proliferation physiology, Female, Humans, Lymphocyte Activation immunology, Male, Signal Transduction immunology, Trypanosoma cruzi, Antigen-Presenting Cells immunology, Antigens, Protozoan immunology, CD3 Complex immunology, Chagas Disease immunology, T-Lymphocytes immunology
- Abstract
Chronic infection by Trypanosoma cruzi decreases T cell proliferation and it is most likely accompanied by changes in signals required for activation. We assessed the effect of T. cruzi antigens on mitogen-induced proliferation of T cells from uninfected individuals and the association with the expression of molecules involved in antigen presentation, T cell costimulation and activation, and cytokine production. T. cruzi antigen exposure reduced mitogen-induced proliferation of CD4+ and CD8+ T cells in PBMC cultures, but only reduced mitogen-induced proliferation in the CD4+ T cells from sorted cell cultures cocultured with antigen-pulsed CD3- cells. CD40/CD80 and CD86 expression were reduced in antigen-pulsed DCs and monocytes, respectively. TNF-α, IL-10 and CCL17 levels were increased in cultures with antigen-pulsed CD3- cells, while CD3ζ chain expression was reduced in T cells from cultures with antigen. Our findings suggest that T. cruzi could alter T cell proliferation indirectly by downregulating costimulatory molecules and inducing the secretion of IL-10 and directly by decreasing TCR signaling., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier Inc. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
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