37 results
Search Results
2. Novel plasma and brain proteins that are implicated in multiple sclerosis.
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Lin, Xin, Yang, Yuanhao, Gresle, Melissa, Cuellar-Partida, Gabriel, Han, Xikun, Stankovich, Jim, Group, AusLong, Simpson-Yap, Steve, Fuh-Ngwa, Valery, Charlesworth, Jac, Burdon, Kathryn P, Butzkueven, Helmut, Taylor, Bruce V, Zhou, Yuan, and AusLong/Ausimmune Investigators Group Steve Simpson-Yap
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BLOOD proteins ,MULTIPLE sclerosis ,KILLER cells ,CYTOTOXIC T cells ,GENOME-wide association studies - Abstract
Understanding how variations in the plasma and brain proteome contribute to multiple sclerosis susceptibility can provide important insights to guide drug repurposing and therapeutic development for multiple sclerosis. However, the role of genetically predicted protein abundance in multiple sclerosis remains largely unknown. Integrating plasma proteomics (n = 3,301) and brain proteomics (n = 376 discovery; n = 152 replication) into multiple sclerosis genome-wide association studies (n = 14,802 cases and 26,703 controls), we employed summary-based methods to identify candidate proteins involved in multiple sclerosis susceptibility. Next, we evaluated associations of the corresponding genes with multiple sclerosis at tissue-level using large gene expression quantitative trait data from whole-blood (n = 31,684) and brain (n = 1,194) tissue. Further, to assess transcriptional profiles for candidate proteins at cell-level, we examined gene expression patterns in immune cell types (dataset 1: n = 73 cases and 97 controls; dataset 2: n = 31 cases and 31 controls) for identified plasma proteins, and in brain cell types (dataset 1: n = 4 cases and 5 controls; dataset 2: n = 5 cases and 3 controls) for identified brain proteins. In a longitudinal multiple sclerosis cohort (n = 203 cases followed up to 15 years), we also assessed the corresponding gene-level associations with the outcome of disability worsening. We identified 39 novel proteins associated with multiple sclerosis risk. Based on five identified plasma proteins, four available corresponding gene candidates showed consistent associations with multiple sclerosis risk in whole-blood, and we found TAPBPL upregulation in multiple sclerosis B cells, CD8+ T cells and natural killer cells compared to controls. Among the 34 candidate brain proteins, 18 were replicated in a smaller cohort and 14 of 21 available corresponding gene candidates also showed consistent associations with multiple sclerosis risk in brain tissue. In cell-specific analysis, six identified brain candidates showed consistent differential gene expression in neuron and oligodendrocyte cell clusters. Based on the 39 protein-coding genes, we found 23 genes that were associated with disability worsening in multiple sclerosis cases. The findings present a set of candidate protein biomarkers for multiple sclerosis, reinforced by high concordance in downstream transcriptomics findings at tissue-level. This study also highlights the heterogeneity of cell-specific transcriptional profiles for the identified proteins, and that numerous candidates were also implicated in disease progression. Together, these findings can serve as an important anchor for future studies of disease mechanisms and therapeutic development. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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3. Manufacture and Characterization of Good Manufacturing Practice-Compliant SARS-COV-2 Cytotoxic T Lymphocytes.
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Chu, Yaya, Milner, Jordan, Lamb, Margaret, Maryamchik, Elena, Rigot, Olivia, Ayello, Janet, Harrison, Lauren, Shaw, Rosemarie, Behbehani, Gregory K, Mardis, Elaine R, Miller, Katherine, Venkata, Lakshmi Prakruthi Rao, Chang, Hsiaochi, Lee, Dean, Rosenthal, Elana, Kadauke, Stephan, Bunin, Nancy, Talano, Julie-An, Johnson, Bryon, and Wang, Yongping
- Subjects
CYTOTOXIC T cells ,SARS-CoV-2 ,MONONUCLEAR leukocytes ,TUMOR necrosis factors ,COVID-19 - Abstract
Background Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 virus-specific cytotoxic T-cell lymphocytes (vCTLs) could provide a promising modality in COVID-19 treatment. We aimed to screen, manufacture, and characterize SARS-CoV-2–vCTLs generated from convalescent COVID-19 donors using the CliniMACS Cytokine Capture System (CCS). Methods Donor screening was done by stimulation of convalescent COVID-19 donor peripheral blood mononuclear cells with viral peptides and identification of interferonγ (IFN-γ)
+ CD4 and CD8 T cells using flow cytometry. Clinical-grade SARS-CoV-2–vCTLs were manufactured using the CliniMACS CCS. The enriched SARS-CoV-2–vCTLs were characterized by T-cell receptor sequencing, mass cytometry, and transcriptome analysis. Results Of the convalescent donor blood samples, 93% passed the screening criteria for clinical manufacture. Three validation runs resulted in enriched T cells that were 79% (standard error of the mean 21%) IFN-γ+ T cells. SARS-CoV-2–vCTLs displayed a highly diverse T-cell receptor repertoire with enhancement of both memory CD8 and CD4 T cells, especially in CD8 TEM, CD4 TCM , and CD4 TEMRA cell subsets. SARS-CoV-2–vCTLs were polyfunctional with increased gene expression in T-cell function, interleukin, pathogen defense, and tumor necrosis factor superfamily pathways. Conclusions Highly functional SARS-CoV-2–vCTLs can be rapidly generated by direct cytokine enrichment (12 hours) from convalescent donors. Clinical Trials Registration NCT04896606. [ABSTRACT FROM AUTHOR]- Published
- 2023
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4. T cell activation and IFNγ modulate organ dysfunction in LPS‐mediated inflammation.
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Taylor, Matthew D., Fernandes, Tiago D., Yaipen, Omar, Higgins, Cassidy E., Capone, Christine A., Leisman, Daniel E., Nedeljkovic‐Kurepa, Ana, Abraham, Mabel N., Brewer, Mariana R., and Deutschman, Clifford S.
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CYTOTOXIC T cells ,T cells ,DENDRITIC cells - Abstract
LPS challenge is used to model inflammation‐induced organ dysfunction. The effects of T cell activation on LPS‐mediated organ dysfunction and immune responses are unknown. We studied these interactions through in vivo administration of anti‐CD3ε (CD3) T cell activating antibody and LPS. Mortality in response to high‐dose LPS (LPSHi; 600 μg) was 60%; similar mortality was observed with a 10‐fold reduction in LPS dose (LPSLo; 60 μg) when administered with CD3 (CD3LPSLo). LPSHi and CD3LPSLo cohorts suffered severe organ dysfunction. CD3LPSLo led to increased IFNγ and IL12p70 produced by T cells and dendritic cells (cDCs) respectively. CD3LPSLo caused cDC expression of CD40 and MHCII and prevented PD1 expression in response to CD3. These interactions led to the generation of CD4 and CD8 cytolytic T cells. CD3LPSLo responded to IFNγ or IL12p40 blockade, in contrast to LPSHi. The combination of TCR activation and LPS (CD3LPSLo) dysregulated T cell activation and increased LPS‐associated organ dysfunction and mortality through T cell and cDC interactions. [ABSTRACT FROM AUTHOR]
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- 2022
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5. Bacillus Calmette-Guerin (BCG) induces superior anti-tumour responses by Vδ2+ T cells compared with the aminobisphosphonate drug zoledronic acid.
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Fenn, J, Ridgley, L A, White, A, Sarfas, C, Dennis, M, Dalgleish, A, Reljic, R, Sharpe, S, and Bodman-Smith, M
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T cells ,ZOLEDRONIC acid ,CELLULAR recognition ,CYTOTOXIC T cells ,CELL populations - Abstract
Vδ2
+ T cells can recognize malignantly transformed cells as well as those infected with mycobacteria. This cross-reactivity supports the idea of using mycobacteria to manipulate Vδ2+ T cells in cancer immunotherapy. To date, therapeutic interventions using Vδ2+ T cells in cancer have involved expanding these cells in or ex vivo using zoledronic acid (ZA). Here, we show that the mycobacterium Bacillus Calmette–Guérin (BCG) also causes Vδ2+ T-cell expansion in vitro and that resulting Vδ2+ cell populations are cytotoxic toward tumour cell lines. We show that both ZA and BCG-expanded Vδ2+ cells effectively killed both Daudi and THP-1 cells. THP-1 cell killing by both ZA and BCG-expanded Vδ2+ cells was enhanced by treatment of targets cells with ZA. Although no difference in cytotoxic activity between ZA- and BCG-expanded Vδ2+ cells was observed, BCG-expanded cells degranulated more and produced a more diverse range of cytokines upon tumour cell recognition compared to ZA-expanded cells. ZA-expanded Vδ2+ cells were shown to upregulate exhaustion marker CD57 to a greater extent than BCG-expanded Vδ2+ cells. Furthermore, ZA expansion was associated with upregulation of inhibitory markers PD-1 and TIM3 in a dose-dependent manner whereas PD-1 expression was not increased following expansion using BCG. Intradermal BCG vaccination of rhesus macaques caused in vivo expansion of Vδ2+ cells. In combination with the aforementioned in vitro data, this finding suggests that BCG treatment could induce expansion of Vδ2+ T cells with enhanced anti-tumour potential compared to ZA treatment and that either ZA or BCG could be used intratumourally as a means to potentiate stronger anti-tumour Vδ2+ T-cell responses. Vd2+ gamma-delta T cells have been shown in vitroto elicit potent cytolytic responses toward tumour cells, suggesting the potential for these responses to be manipulated in cancer immunotherapy. We show that heat-killed Bacillus Calmette-Guerin (HKBCG) promotes the expansion of Vd2+ T cells both in vitroand in vivo. These HKBCG-expanded cells exhibited enhanced degranulation and cytokine production in tumour cells compared to cells expanded using bisphosphonates. [ABSTRACT FROM AUTHOR]- Published
- 2022
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6. Patho-immunological mechanisms of vitiligo: the role of the innate and adaptive immunities and environmental stress factors.
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Faraj, Safa, Kemp, Elizabeth Helen, and Gawkrodger, David John
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PSYCHONEUROIMMUNOLOGY ,VITILIGO ,NATURAL immunity ,CHROMATOPHORES ,EMOTIONAL trauma ,ANTIGEN presentation - Abstract
Epidermal melanocyte loss in vitiligo, triggered by stresses ranging from trauma to emotional stress, chemical exposure or metabolite imbalance, to the unknown, can stimulate oxidative stress in pigment cells, which secrete damage-associated molecular patterns that then initiate innate immune responses. Antigen presentation to melanocytes leads to stimulation of autoreactive T-cell responses, with further targeting of pigment cells. Studies show a pathogenic basis for cellular stress, innate immune responses and adaptive immunity in vitiligo. Improved understanding of the aetiological mechanisms in vitiligo has already resulted in successful use of the Jak inhibitors in vitiligo. In this review, we outline the current understanding of the pathological mechanisms in vitiligo and locate loci to which therapeutic attack might be directed. [ABSTRACT FROM AUTHOR]
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- 2022
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7. Regeneration of antigen-specific T cells by using induced pluripotent stem cell (iPSC) technology.
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Kawamoto, Hiroshi, Masuda, Kyoko, and Nagano, Seiji
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INDUCED pluripotent stem cells ,T cells ,CYTOTOXIC T cells ,REGENERATION (Biology) ,ACUTE myeloid leukemia - Abstract
In currently ongoing adoptive T-cell therapies, T cells collected from the patient are given back to the patient after ex vivo cell activation and expansion. In some cases, T cells are transduced with chimeric antigen receptor (CAR) or T-cell receptor (TCR) genes during the ex vivo culture period. Although such strategies have been shown to be effective in some types of cancer, there remain issues to be solved; these methods (i) are time-consuming, (ii) are costly and (iii) it is difficult to guarantee the quality because the products depend on patient-derived T cells. To address these issues, several groups including ours have developed methods in which cytotoxic cells are mass-produced by using induced pluripotent stem cell (iPSC) technology. For the regeneration of T cells, the basic idea is as follows: iPSCs produced from T cells inherit rearranged TCR genes, and thus all regenerated T cells should express the same TCR. Based on this idea, various types of T cells have been regenerated, including conventional cytotoxic T lymphocytes (CTLs), γδT cells, NKT cells and mucosal-associated invariant T (MAIT) cells. On the other hand, any cytotoxic cells can be used as the base cells into which CAR is introduced, and thus iPSC-derived NK cells have been developed. To apply the iPSC-based cell therapy in an allogeneic setting, the authors' group developed a method in which non-T-cell-derived iPSCs are transduced with exogenous TCR genes (TCR-iPSC method). This approach is being prepared for a clinical trial to be realized in Kyoto University Hospital, in which acute myeloid leukemia patients will be treated by the regenerated WT1 antigen-specific CTLs. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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8. Inhibition of GFAT1 in lung cancer cells destabilizes PD-L1 protein.
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Chen, Wenshu, Saxton, Bryanna, Tessema, Mathewos, and Belinsky, Steven A
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CANCER cells ,GLUTAMINE ,LUNG cancer ,PROGRAMMED death-ligand 1 ,CYTOTOXIC T cells ,PROTEIN stability - Abstract
Immunotherapy using checkpoint blockers (antibodies) has been a major advance in recent years in the management of various types of solid cancers including lung cancer. One target of checkpoint blockers is programmed death ligand 1 (PD-L1) expressed by cancer cells, which engages programmed death 1 on T cells and Natural Killer (NK) cells resulting in suppression of their activation and cancer-killing function, respectively. Apart from antibodies, other clinically relevant agents that can inhibit PD-L1 are limited. PD-L1 protein stability depends on its glycosylation. Here we show that l-glutamine:d-fructose-6-phosphate amidotransferase 1 (GFAT1), a rate-limiting enzyme of the hexosamine biosynthesis pathway, which produces uridine diphosphate- N -acetyl-β-glucosamine, a precursor for glycosylation, is required for the stability of PD-L1 protein. Inhibition of GFAT1 activity markedly reduced interferon gamma (IFNγ)-induced PD-L1 levels in various lung cancer cell lines. GFAT1 inhibition suppressed glycosylation of PD-L1 and accelerated its proteasomal degradation. Importantly, inhibition of GFAT1 in IFNγ-treated cancer cells enhanced the activation of T cells and the cancer-killing activity of NK cells. These findings support using GFAT1 inhibitors to manipulate PD-L1 protein level that could augment the efficacy of immunotherapy for lung cancer. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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9. IFNγ‐mediated repression of system xc− drives vulnerability to induced ferroptosis in hepatocellular carcinoma cells.
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Kong, Rui, Wang, Nan, Han, Wei, Bao, Wen, and Lu, Jie
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HEPATOCELLULAR carcinoma ,KILLER cells ,CYTOTOXIC T cells ,REACTIVE oxygen species ,CELL cycle - Abstract
IFNγ released from CD8+ T cells or natural killer cells plays a crucial role in antitumor host immunity. Several studies have found that IFNγ is involved in regulating tumor cell proliferation and apoptosis. However, few studies have examined its role in cell ferroptosis. Here, we found that IFNγ treatment enhanced glutathione depletion, promoted cell cycle arrested in G0/G1 phase, increased lipid peroxidation, and sensitized cells to ferroptosis activators. Additionally, IFNγ down‐regulated the mRNA and protein levels of SLC3A2 and SLC7A11, two subunits of the glutamate‐cystine antiporter system xc− via activating the JAK/STAT pathway in hepatocellular carcinoma (HCC) cell lines. Furthermore, IFNγ increased reactive oxygen species levels and decreased mitochondiral membrane potential in Bel7402 and HepG2 cells. These changes were accompanied by decreased system xc− activity. Cancer cells exposed to TGFβ1 for 48 h showed sensitization to IFNγ + erastin‐induced ferroptosis, with decreased system xc− expression. In conclusion, IFNγ repressed system xc− activation via activating JAK/STAT signaling. Additionally, enhanced lipid peroxidation was associated with altered mitochondrial function in HCC cells. Our findings identified a role for IFNγ in sensitizing HCC cells to ferroptosis, which provided new insights for applying IFNγ as a cancer treatment. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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10. Lipid antigens in bile from patients with chronic liver diseases activate natural killer T cells.
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Valestrand, L., Berntsen, N. L., Zheng, F., Schrumpf, E., Hansen, S. H., Karlsen, T. H., Blumberg, R. S., Hov, J. R., Jiang, X., and Melum, E.
- Subjects
CYTOTOXIC T cells ,KILLER cells ,CHRONICALLY ill ,BILE ,ANTIGENS - Abstract
Summary: Natural killer T (NKT) cells are an abundant subset of liver lymphocytes activated by lipid antigens presented on CD1d molecules that are expressed by cholangiocytes. We aimed to determine if bile from patients with chronic liver diseases contains antigenic lipids that can activate NKT cells. Using murine invariant (24.7, 24.8 and DN32.D3) and non‐invariant (14S.6, 14S.7 and 14S.10) NKT hybridomas we investigated the presence of lipid antigens in bile collected from the gallbladder of patients undergoing liver transplantation due to end‐stage liver disease. Biliary microbiota profiles were generated using 16S rRNA amplicon sequencing. We found that the patient bile samples contain antigens that activate both invariant and non‐invariant NKT hybridomas (24.7, 24.8, DN32.D3, 14S.6, 14S.7 and 14S.10), as demonstrated by activation of at least one hybridoma by eight of 10 bile samples. Activation at high dilutions suggests that some antigens are highly potent. We used the non‐invariant NKT hybridoma 14S.6 to screen 21 additional patient bile samples for NKT‐reactivity and demonstrated that 12 of 21 bile samples resulted in activation, three of which gave a strong activation. Four of 12 activating bile samples contained microbial DNA. Our results reveal an immunological pathway that could be of critical importance in biliary immunology. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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11. Interleukin‐35 has a tumor‐promoting role in hepatocellular carcinoma.
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Liu, X., Ren, H., Guo, H., Wang, W., and Zhao, N.
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CYTOTOXIC T cells ,HEPATOCELLULAR carcinoma ,SUPPRESSOR cells ,T cells ,CELL physiology - Abstract
Summary: Hepatic inflammatory response is a risk factor for liver cancer initiation and progression. Interleukin (IL)‐35 is the newest member of the IL‐12 cytokine family, and has been reported to play an essential role in the immunosuppressive liver microenvironment. Herein we focus on the expression profiles of IL‐35 in hepatocellular carcinoma (HCC) and effects on local immune status. HCC transcriptome array data were downloaded from Gene Expression Omnibus (GEO). Analysis was performed by BRB‐Array Tools and Ingenuity Pathway Analysis (IPA) software. Serum IL‐35 level was detected by AimPlet bead‐based immunoassay. In‐situ IL‐35 detection was performed by immunohistochemical staining and Western blot. The n‐vitro effect of IL‐35 on CD4+ or CD8+ T cell function was detected by flow cytometry. Our results showed that there were large amounts of IL‐35 expressed in HCC serum and tumor tissues. IL‐35 expression affects the transcript of thousands of genes, most differentially expressed genes (DEGs), in tumor tissues correlated with T cell immunity. The IL‐35 high‐expression group exhibited enhancement of regulatory T cells (Tregs) and impairment of cytolytic T cells. In‐vitro experiments proved that exogenous IL‐35 stimulated the expression of programmed cell death 1 (PD‐1) and lymphocyte activation gene‐3 (LAG3) in CD4+ and CD8+ T cells. In addition, the stimulating effect was time‐dependent. Furthermore, IL‐35 inhibited interferon (IFN)‐γ secretion by CD4+ and CD8+ T cells. Elevated IL‐35 had an immune suppressive role in HCC tumor microenvironments through affecting inhibitor receptor expression and cytokine secretion of CD4+ and CD8+ T cells. Dissection of the precise targets and underlying molecular mechanisms would mean alternative treatments for HCC patients. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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12. Transforming growth factor beta orchestrates PD-L1 enrichment in tumor-derived exosomes and mediates CD8 T-cell dysfunction regulating early phosphorylation of TCR signalome in breast cancer.
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Chatterjee, Soumya, Chatterjee, Annesha, Jana, Samir, Dey, Subhasis, Roy, Himansu, Das, Mrinal Kanti, Alam, Jahirul, Adhikary, Anindya, Chowdhury, Abhisek, Biswas, Anupam, Manna, Debasis, and Bhattacharyya, Arindam
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TRANSFORMING growth factors-beta ,PROGRAMMED death-ligand 1 ,CYTOTOXIC T cells ,EXOSOMES ,PHOSPHORYLATION - Abstract
Tumor cells promote immune evasion through upregulation of programmed death-ligand 1 (PD-L1) that binds with programmed cell death protein 1 (PD1) on cytotoxic T cells and promote dysfunction. Though therapeutic efficacy of anti-PD1 antibody has remarkable effects on different type of cancers it is less effective in breast cancer (BC). Hence, more details understanding of PD-L1-mediated immune evasion is necessary. Here, we report BC cells secrete extracellular vesicles in form of exosomes carry PD-L1 and are highly immunosuppressive. Transforming growth factor beta (TGF-β) present in tumor microenvironment orchestrates BC cell secreted exosomal PD-L1 load. Circulating exosomal PD-L1 content is highly correlated with tumor TGF-β level. The later also found to be significantly associated with CD8+CD39+, CD8+PD1+ T-cell phenotype. Recombinant TGF-β1 dose dependently induces PD-L1 expression in Texos in vitro and blocking of TGF-β dimmed exosomal PD-L1 level. PD-L1 knocked down exosomes failed to suppress effector activity of activated CD8 T cells like tumor exosomes. While understanding its effect on T-cell receptor signaling, we found siPD-L1 exosomes failed to block phosphorylation of src family proteins, linker for activation of T cells and phosphoinositide phospholipase Cγ of CD8 T cells more than PD-L1 exosomes. In vivo inhibition of exosome release and TGF-β synergistically attenuates tumor burden by promoting Granzyme and interferon gamma release in tumor tissue depicting rejuvenation of exhausted T cells. Thus, we establish TGF-β as a promoter of exosomal PD-L1 and unveil a mechanism that tumor cells follow to promote CD8 T-cell dysfunction. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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13. Increased O-GlcNAcylation prevents degeneration of dopamine neurons.
- Author
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Hart, Gerald W and Huang, Chia-Wei
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DOPAMINERGIC neurons ,NEURODEGENERATION ,T helper cells ,CYTOTOXIC T cells ,LACUNAR stroke ,PARKINSON'S disease ,COMPARATIVE studies ,GLYCOSYLATION ,RESEARCH methodology ,MEDICAL cooperation ,NEURONS ,PHOSPHORYLATION ,RESEARCH ,EVALUATION research - Published
- 2020
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14. Novel actors on the stage of cardiac dysfunction induced by anti-PD1 oncological treatments.
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Varricchi, Gilda, Galdiero, Maria Rosaria, and Tocchetti, Carlo G
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CARDIOTOXICITY ,IMMUNE checkpoint inhibitors ,MONOCLONAL antibodies ,PROGRAMMED death-ligand 1 ,CYTOTOXIC T cells - Abstract
An editorial is presented on targeting early stages of cardiotoxicity from anti-PD1 immune checkpoint inhibitor therapy. Topics include cancer immunotherapies with monoclonal antibodies (mAbs) against immune checkpoints and programmed death 1 (PD1) improving antineoplastic treatments; and causing autoimmune myocarditis with lymphocytic infiltration of cytotoxic T cells suggesting molecules having a major role in preventing autoimmunity.
- Published
- 2022
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15. Interview with Dr Toshio Hirano.
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CLINICAL immunology ,COVID-19 ,CYTOLOGY ,CYTOTOXIC T cells ,B cells ,SYSTEMIC lupus erythematosus - Published
- 2021
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16. Interview with Dr Kazuo Sugamura.
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INTERLEUKIN-2 ,CYTOTOXIC T cells ,INDIGENOUS peoples of South America ,COVID-19 - Published
- 2021
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17. Assessment of immunization regimens of duck Riemerella anatipestifer vaccines.
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Wu, H.-C., Chang, W.-C., Wu, M.-C., Wang, H.-Y., and Chu, C.-Y.
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CD8 antigen ,IMMUNIZATION ,CYTOTOXIC T cells ,DNA primers ,VACCINE development ,VACCINES ,INTERLEUKIN-6 - Abstract
Aims: Riemerella anatipestifer infections of goslings and ducklings can result in high mortality. Since there are at least 21 serotypes of R. anatipestifer, crossprotection is an important goal for vaccine development. Methods and Results: In this study, we evaluated the immunostimulatory effect of different immunization regimens -- the traditional inactivated vaccine vs prime--boost regimens using DNA and protein subunit vaccines (DNA+subunit, subunit+subunit, subunit+inactivated and DNA+DNA). Results showed that, when compared to the inactivated vaccine, prime--boost regimens induced higher and up to 16-week longer lasting levels of antibody responses, significantly elevated the percentage of the cytotoxic CD8+ T cell and higher expression levels of IFN-c, IL-6 and IL-12 mRNAs. Furthermore, as an indication of cross-protection, sera from prime--boost regimens were able to recognize lysates of R. anatipestifer serotypes 1, 2 and 6. Conclusions: Prime--boost regimens especially DNA-prime and protein-boost, induce strong long-term immune response and may prove protective for breeder ducks requiring long-term protection. Significance and Impact of the Study: It is worth mentioning that the subunit+inactivated regimen group also elicited strong immune response. The cost of this regimen may only be half of the other prime--boost regimens, making this subunit + inactivated combination an attractive option. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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18. HBV‐specific CD8 T cells present higher TNF‐α expression but lower cytotoxicity in hepatocellular carcinoma.
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Zhao, L., Jin, Y., Yang, C., and Li, C.
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T cells ,PERFORINS ,CYTOTOXIC T cells ,HEPATOCELLULAR carcinoma ,CHRONIC hepatitis B ,TUMOR necrosis factors - Abstract
Summary: Tumor necrosis factor (TNF)‐α is largely regarded as a proinflammatory cytokine, but several recent researches have demonstrated that TNF‐α could possess immunoregulatory roles with potential to suppress anti‐tumor immunity. Chronic hepatitis B virus (HBV) infection is a major risk factor of hepatocellular carcinoma (HCC), and HBV‐specific CD8 T cells could exert anti‐tumor roles in HCC patients. Here, we found that HBV‐specific CD8 T cells, both in the peripheral blood and in the tumor microenvironment, were more enriched with TNF‐α‐expressing cells than interferon (IFN)‐γ‐expressing cells. Compared to IFN‐γ‐expressing HBV‐specific CD8 T cells, TNF‐α‐expressing HBV‐specific CD8 T cells presented lower expression of inhibitory checkpoint molecules, including programmed cell death (PD)‐1, T cell immunoglobulin mucin‐3 (TIM‐3) and cytotoxic T lymphocyte antigen (CTLA)‐4. HBV‐specific CD8 T cells could mediate the lysis of autologous primary tumor cells, and the inhibition of TNF‐α could further elevate their cytotoxic capacity. Subsequently, we demonstrated that TNF‐α inhibition in HBV‐specific CD8 T cells could significantly increase granzyme B (GZMB) and perforin 1 (PRF1) expression while having no effect towards granzyme A (GZMA) expression. The addition of exogenous TNF‐α at low levels had no consistent effect on the expression of GZMA, GZMB and PRF1, but at higher levels, exogenous TNF‐α significantly reduced GZMA, GZMB and PRF1 expression. Overall, these results suggested that TNF‐α‐expressing cells probably presented a deleterious role in HCC but were enriched in HBV‐specific CD8 T cells. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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19. T11TS immunotherapy potentiates the repressed calcineurin‐NFAT signalling pathway of T cells in Cryptococcus neoformans infected rats: a cue towards T‐cell activation for antifungal immunity.
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Omar Faruk, S.M., Hazra, I., Mondal, S., Datta, A., Moitra, S., Das, P.K., Mishra, R., and Chaudhuri, S.
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T cells ,CRYPTOCOCCUS neoformans ,IMMUNOTHERAPY ,IMMUNITY ,MYCOSES ,CYTOTOXIC T cells - Abstract
Aims: To examine the modulation of the interacting partners of the calcineurin (CaN)‐NFAT pathway in T cells during Cryptococcus neoformans fungal infection and post‐T11TS immunotherapy. Methods and Results: Wistar rats were infected with C. neoformans and followed by immunotherapy with immune‐potentiator T11TS. T cells were analysed by flow cytometry, immunoblotting and nuclear translocation study. The signalling proteins LCK, FYN, LAT, PLCγ1 and CaN in T cells were regulated by C. neoformans infection resulting in reduced nuclear translocation of NFAT and IL‐2 expression. Following T11TS immunotherapy, the expressions of the above‐mentioned proteins were boosted and thus resulting in the clearance of C. neoformans from lung and spleen. Conclusions: The precise mechanism of suppression of the T‐cell function by C. neoformans is still unknown. Previously, we have shown that T11TS positively regulates the function of T cells to abrogate glioma and other immunosuppressive conditions. T11TS immunotherapy increased the expression of the above signalling partners of the CaN‐NFAT pathway in T cells and improved nuclear retention of NFAT. As a result, an increased IL‐2 expression leads to activation and proliferation of T cells. Significance and Impact of the Study: Our results demonstrate the role of T11TS in restoring the CaN‐NFAT signalling pathway in T cells. It identifies T11TS as an immunotherapeutic agent with potential clinical outcomes to counteract C. neoformans infection. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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20. VISTA: Coming of age as a multi‐lineage immune checkpoint.
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ElTanbouly, M. A., Schaafsma, E., Noelle, R. J., and Lines, J. L.
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CYTOTOXIC T cells ,COMING of age ,SUPPRESSOR cells ,T cells ,TUMOR growth - Abstract
Summary: The immune response is governed by a highly complex set of interactions among cells and mediators. T cells may be rendered dysfunctional by the presence of high levels of antigen in the absence of co‐stimulation while myeloid cells may be programmed towards an immunosuppressive state that promotes cancer growth and metastasis while deterring tumor immunity. In addition, inhibitory programs driven by immune checkpoint regulators dampen anti‐tumor immunity. The ideal cancer immunotherapy treatment will improve both cross‐priming in the tumor microenvironment and relieve suppression by the inhibitory checkpoints. Recently, blockade of programmed cell death 1 (PD‐1) and cytotoxic T lymphocyte antigen 4 (CTLA‐4) has elicited impressive results, but not in all patients, so additional targets are under investigation. V‐set immunoglobulin domain suppressor of T cell activation (VISTA) is a novel immunoregulatory receptor that is broadly expressed on cells of the myeloid and lymphoid lineages, and is frequently implicated as a poor prognostic indicator in multiple cancers. Importantly, antibody targeting of VISTA uniquely engages both innate and adaptive immunity. This, combined with the expression of VISTA and its non‐redundant activities compared to other immune checkpoint regulators, qualifies VISTA to be a promising target for improving cancer immunotherapy. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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21. Mechanisms of checkpoint inhibition‐induced adverse events.
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Urwyler, P., Earnshaw, I., Bermudez, M., Perucha, E., Wu, W., Ryan, S., Mcdonald, L., Karagiannis, S. N., Taams, L. S., Powell, N., Cope, A., and Papa, S.
- Subjects
CYTOTOXIC T cells ,NON-small-cell lung carcinoma ,FORECASTING ,IMMUNE checkpoint inhibitors ,DRUG side effects ,PROGRAMMED cell death 1 receptors ,DRUG toxicity ,MELANOMA - Abstract
Summary: Immune checkpoint inhibition has revolutionized the treatment of several solid cancers, most notably melanoma and non‐small‐cell lung cancer (NSCLC). Drugs targeting cytotoxic T lymphocyte antigen (CTLA)‐4 and programmed cell death 1 (PD‐1) have made their way into routine clinical use; however, this has not been without difficulties. Stimulation of the immune system to target cancer has been found to result in a reduction of self‐tolerance, leading to the development of adverse effects that resemble autoimmunity. These adverse effects are erratic in their onset and severity and can theoretically affect any organ type. Several mechanisms for immune‐related toxicity have been investigated over recent years; however, no consensus on the cause or prediction of toxicity has been reached. This review seeks to examine reported evidence for possible mechanisms of toxicity, methods for prediction of those at risk and a discussion of future prospects within the field. [ABSTRACT FROM AUTHOR]
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- 2020
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22. Knowledge is power—Rational design of cancer immunotherapy.
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De Paris, Kristina
- Subjects
SUPPRESSOR cells ,CYTOTOXIC T cells - Abstract
Tumor-induced immune evasion mechanisms, such as the induction of soluble immunosuppressive factors, the recruitment of regulatory T cells, and tumor antigen mutations, further limit tumor-specific CD8 SP + sp T cell responses. The figure illustrates the pathway of CD8+ T cell differentiation in response to tumor antigen (Ag) exposure from a naïve (TN) to activated (Tact) CD8+ T cells, that will then undergo massive expansion to early effector CD8+ T cells (Tearly Eff). Adoptive cell transfer therapies, including CAR T cell therapy, often start with CD8+ effector T cells that already exhibit signs of functional impairment, and therefore only result in partial tumor regression (dashed red lines). Transition of late-stage effector T cells to CD27+ CD28+ tumor-reactive effector memory T cells in humans after adoptive cell transfer therapy. [Extracted from the article]
- Published
- 2019
- Full Text
- View/download PDF
23. Tumour necrosis factor α augments the inhibitory effects of CTLA‐4‐Ig on osteoclast generation from human monocytes via induction of CD80 expression.
- Author
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Oi, K., Tokunaga, T., Kuranobu, T., Yukawa, K., Kohno, H., Yoshida, Y., Mokuda, S., Hirata, S., and Sugiyama, E.
- Subjects
OSTEOCLASTS ,TRANCE protein ,MONOCYTES ,CYTOTOXIC T cells ,SYNOVIAL fluid ,MACROPHAGE colony-stimulating factor - Abstract
Summary: Cytotoxic T lymphocyte antigen‐4‐immunoglobulin (CTLA‐4‐Ig) exerts anti‐rheumatic action via negative regulation of the co‐stimulation process between antigen‐presenting cells and T cells. CTLA‐4‐Ig also binds to CD80/CD86 on monocytes of osteoclast precursors. However, little is known about the effect of CTLA‐4‐Ig on osteoclastogenesis in rheumatoid arthritis (RA). In this study we evaluated the effects of CTLA‐4‐Ig on osteoclast generation from human blood monocytes (PBM) and rheumatoid synovial fluid monocytes (RSFM). Highly purified monocytes were cultured with receptor activator of nuclear factor kappa‐B ligand (RANKL) and macrophage colony‐stimulating factor (M‐CSF) in the presence of CTLA‐4‐Ig. CTLA‐4‐Ig inhibited RANKL‐induced osteoclast generation in PBM and RSFM, as determined by tartrate‐resistant acid phosphatase (TRAP) staining and bone resorption assay using osteo assay surface plates. In addition, CTLA‐4‐Ig reduced the gene and protein expressions of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) and cathepsin K during osteoclastogenesis. Furthermore, CTLA‐4‐Ig significantly inhibited cell proliferation during osteoclastogenesis. Interestingly, the gene expression of indoleamine 2,3‐dioxygenase‐1, an inducer of apoptosis, was enhanced by CTLA‐4‐Ig. We next examined the effect of tumour necrosis factor (TNF)‐α, a major inflammatory cytokine in rheumatoid synovium, on the expression of CD80 and CD86 by flow cytometric analysis. TNF‐α potently induced the surface expression of CD80, which is known to have much higher affinity to CTLA‐4‐Ig than CD86, and this induction was observed at mRNA levels. Interestingly, freshly prepared rheumatoid synovial monocytes also expressed CD80 as much as TNF‐α‐treated PBM. Furthermore, TNF‐α enhanced CTLA‐4‐Ig‐induced inhibition of osteoclastogenesis and cell proliferation. Taken together, the TNF‐α‐induced CD80 may augment CTLA‐4‐Ig‐induced inhibition of osteoclastogenesis, suggesting that CTLA‐4‐Ig potently inhibits osteoclast differentiation and protects bone destruction in rheumatoid inflamed joints. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
24. Why, when and how should exposure be considered at the within-host scale? A modelling contribution to PRRSv infection.
- Author
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Go, Natacha, Belloc, Catherine, Bidot, Caroline, and Touzeau, Suzanne
- Subjects
PORCINE reproductive & respiratory syndrome ,INFECTION ,CYTOTOXIC T cells ,HUMORAL immunity ,BIOLOGICAL mathematical modeling ,ANTIGEN presenting cells - Published
- 2019
- Full Text
- View/download PDF
25. High concentrations of atorvastatin reduce in‐vitro function of conventional T and regulatory T cells.
- Author
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Rodríguez‐Perea, A. L., Rojas, M., and Velilla‐Hernández, P. A.
- Subjects
T cells ,CYTOTOXIC T cells ,ATORVASTATIN ,FORKHEAD transcription factors ,PERFORINS ,IMMUNOLOGIC diseases - Abstract
Summary: Regulatory T cells (Tregs) modulate the magnitude of immune responses and possess therapeutic potential in an array of immune diseases. Statins reduce the activation and proliferation of conventional T cells (Tcons), and they seem to up‐regulate the frequency and function of Tregs. However, there is a lack of simultaneous evaluation of the in‐vitro effect of statins on the functional profile of Tregs versus Tcons. Herein, magnetically purified Tcons and Tregs were stimulated with CD3/CD28/interleukin (IL)‐2 in the presence of atorvastatin (ATV) at 1 or 10 µM. The suppressive function of Tregs, the expression of markers associated with Treg function, activation levels, cytokine production and calcium flux in both subpopulations were assessed by flow cytometry. ATV had no cytotoxic effect on T cells at the concentrations used. Interestingly, 10 µM ATV hampered the suppressive capacity of Tregs. Moreover, this higher concentration reduced the expression of forkhead box protein 3 (FoxP3), cytotoxic T lymphocyte antigen (CTLA‐4) and programmed death 1 (PD‐1). In Tcons, ATV at 10 µM decreased PD‐1 and CD45RO expression. The expression of CD25, CD69, CD95, CD38, CD62L, CCR7 and perforin was not affected in both subpopulations or at any ATV concentrations. Remarkably, 10 µM ATV increased the percentage of tumour necrosis factor (TNF)‐α‐producing Tregs. Although there was a reduction of calcium flux in Tcons and Tregs, it was only significant in 10 µM ATV‐treated Tcons. These results suggested that 10 µM ATV affects the cellular functions of both populations; however, this concentration particularly affected several aspects of Treg biology: its suppressive function, cytokine production and expression of Treg‐specific markers. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
26. Granulysin- and granzyme-dependent elimination of myeloid cells by therapeutic ova-specific type 1 regulatory T cells.
- Author
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Guipouy, Delphine, Gertner-Dardenne, Julie, Pfajfer, Laurène, German, Yolla, Belmonte, Nathalie, and Dupré, Loïc
- Subjects
GRANZYMES ,CYTOTOXIC T cells ,MYELOID differentiation factor 88 ,T cells ,CROHN'S disease ,DENDRITIC cells ,CELLS ,CELL populations - Abstract
The intrinsic immunosuppressive properties of regulatory T (Treg) cells can be harnessed for therapeutic approaches aiming at down-modulating harmful immune reactions. In this context, expanded type 1 Treg cells (Tr1 cells) specific for ovalbumin (ova-Tr1 cells) have been tested for clinical efficacy in the treatment of autoimmune disorders such as refractory Crohn's disease (CD). The clinical use of these therapeutic products warrants exploration of their mechanism of action. Here, we identified a relationship between the CD activity index and the expression of lytic molecules by the ova-Tr1 cells administered in the previously reported First-in-Man study [Crohn's And Treg cells Study 1 (CATS1) study]. Accordingly, ova-Tr1 cells were found to carry granules containing high levels of lytic molecules, including multiple granzymes and granulysin. These cells displayed a T-cell receptor (TCR)-independent cytotoxic activity, which was preferentially directed toward myeloid cell lines and monocyte-derived dendritic cells. Upon contact with myeloid cells, ova-Tr1 cells induced their apoptosis via a perforin-independent and a granulysin/granzyme-dependent mechanism. As compared to CD8
+ cytotoxic T cells, ova-Tr1 cells required more time to lyse target cells and displayed a more gradual lytic activity over time. Notably, this activity was sustained over days resulting in the control of myeloid cell populations at a relatively low ratio. Our study reveals that ova-Tr1 cells are endowed with a sustained cytotoxic activity that relies on a unique combination of granulysin and granzymes and that preferentially eliminates myeloid target cells in a TCR-independent manner. [ABSTRACT FROM AUTHOR]- Published
- 2019
- Full Text
- View/download PDF
27. Immunophenotype involved in IgG4-related disease.
- Author
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Satoshi Kubo, Shingo Nakayamada, and Yoshiya Tanaka
- Subjects
IMMUNOGLOBULINS ,LYMPHOCYTES ,IMMUNOPHENOTYPING ,IMMUNOCOMPETENT cells ,CYTOTOXIC T cells - Abstract
As stated in the comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), IgG4-RD is characterized by elevated serum IgG4 level and pathological findings, characterized by infiltration of IgG4-positive plasma cells. In addition to fibrotic changes, dysregulated activation of lymphocytes is considered as one of major pathogenic events in IgG4-RD. Among lymphocytes, the importance of plasmablast, T follicular helper (Tfh) cells, T type 2 helper (Th2) cells, T regulatory (Treg) cells, and CD4 positive T cells with cytotoxic activity has been reported. Conversely, comprehensive immunophenotyping in patients with IgG4-RD revealed that there are two different axes consisting plasmablast-Tfh cells and Treg cells. There is need for research to seek out molecules associated with these immunocompetent cell interactions. It is believed that this will contribute to the future application to diseasespecific treatment for IgG4-RD. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
28. Submicroscopic Plasmodium infection during pregnancy is associated with reduced antibody levels to tetanus toxoid.
- Author
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Álvarez‐Larrotta, C., Agudelo, O.M., Duque, Y., Gavina, K., Yanow, S.K., Maestre, A., Carmona‐Fonseca, J., and Arango, E.
- Subjects
FORKHEAD transcription factors ,CYTOTOXIC T cells ,TRANSFORMING growth factors ,TETANUS ,PLASMODIUM - Abstract
Summary: Submicroscopic Plasmodium infections in pregnancy are common in endemic areas, and it is important to understand the impact of these low‐level infections. Asymptomatic, chronic infections are advantageous for parasite persistence, particularly in areas where the optimal eco‐epidemiological conditions for parasite transmission fluctuate. In chronic infections, the persistence of the antigenic stimulus changes the expression of immune mediators and promotes constant immune regulation, including increases in regulatory T cell populations. These alterations of the immune system could compromise the response to routine vaccination. This study aimed to evaluate the effect of submicroscopic plasmodial infection with P. falciparum and P. vivax during pregnancy on the immune response to the tetanus toxoid vaccine in Colombian women. Expression of different cytokines and mediators of immune regulation and levels of anti‐tetanus toxoid (TT) immunoglobulin (Ig)G were quantified in pregnant women with and without submicroscopic plasmodial infection. The anti‐TT IgG levels were significantly lower in the infected group compared with the uninfected group. The expression of interferon (IFN)‐γ, tumour necrosis factor (TNF) and forkhead box protein 3 (FoxP3) was significantly higher in the infected group, while the expression of cytotoxic T lymphocyte antigen 4 (CTLA‐4) and transforming growth factor (TGF)‐β was lower in the group of infected. In conclusion, submicroscopic Plasmodium infection altered the development of the immune response to the TT vaccine in Colombian pregnant women. The impact of Plasmodium infections on the immune regulatory pathways warrants further exploration. Submicroscopic plasmodial infection in pregnancy (SPIP) is associated with reduced antibody levels to tetanus toxoid in Colombian women, which could be explained by the inclination towards a regulatory profile of the immune response generated in those chronic plasmodial infections. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
29. Transcriptional and epigenetic regulation of T cell hyporesponsiveness.
- Author
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Pereira, Renata M., Hogan, Patrick G., Rao, Anjana, and Martinez, Gustavo J.
- Subjects
CYTOTOXIC T cells ,T cells ,CELLULAR control mechanisms ,MEMORY ,HYPOPHARYNGEAL cancer ,RECEPTOR antibodies ,TRANSCRIPTION factors - Abstract
Review on the transcriptional and epigenetic programs driving hyporesponsive states in T cells. Naive CD8+ T cells differentiate into effector and memory cytolytic T cells (CTLs) during an acute infection. In contrast, in scenarios of persistent antigen stimulation, such as chronic infections and cancer, antigen‐specific CTLs show a gradual decrease in effector function, a phenomenon that has been termed CD8+ T cell "exhaustion" or "dysfunction." Another hyporesponsive state, termed "anergy", is observed when T cells are activated in the absence of positive costimulatory signals. Among the many negative regulators induced in hyporesponsive T cells are inhibitory cell–surface receptors, such as PD‐1, LAG‐3, CTLA‐4, and TIM‐3; "checkpoint blockade" therapies that involve treatment of patients with cancer with blocking antibodies to those receptors show considerable promise in the clinic because the blocking antibodies can mitigate hyporesponsiveness and promote tumor rejection. In this review, we describe recent advances in our molecular understanding of these hyporesponsive states. We review evidence for the involvement of diverse transcription factors, metabolic programs, and chromatin accessibility changes in hyporesponsive T cells, and we discuss how checkpoint blockade therapies affect the molecular program of CD8+ T cell exhaustion. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
30. Advantage of tacrolimus/mycophenolate mofetil regimen for cytotoxic T cell-mediated defence and its inhibition by additive steroid administration in high-risk liver transplant recipients.
- Author
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Uemoto, S., Ozawa, K., Kaido, T., Mori, A., and Fujimoto, Y.
- Subjects
TACROLIMUS ,MYCOPHENOLIC acid ,CYTOTOXIC T cells ,ANABOLIC steroids ,LIVER transplantation ,STEROID drugs ,DRUG administration ,PATIENTS - Abstract
Our previous work revealed that the recipients with the highest pre-existing numbers of CD8
+ effector T cells (TE ) [hyperparathyroidism (HPT)E recipients] occupied approximately 30% of adult transplant recipients performed in our hospital. HPTE recipients demonstrated very poor clinical outcome compared with the remaining 70% of recipients with the lowest pre-existing TE (LPTE recipient). This study aimed to clarify the best combined immunosuppressive regimen related to function of cytotoxic T lymphocytes (CTLs) for HPTE recipients. Eighty-one HPTE recipients were classified into three types, according to the immunosuppressive regimens: type 1, tacrolimus (Tac)/glucocorticoid (GC); type 2, Tac/mycophenolate mofetil (MMF)/GC; and type 3, Tac/MMF. Frequencies of severe infection, rejection and hospital death were the highest in types 1 and 2, whereas the lowest occurred in type 3. The survival rate in type 3 was the highest (100%) during follow-up until post-operative day 2000. Regarding the immunological mechanism, in type 1 TE perforin and interferon (IFN)-γ were generated through the self-renewal of CD8+ central memory T cells (TCM ), but decreased in the early post-transplant period due to marked down-regulation of interleukin (IL)-12 receptor beta-1 of TCM. In type 2, the self-renewal TCM did not develop, and the effector function could not be increased. In type 3, in contrast, the effectors and cytotoxicity were correlated inversely with IL-12Rβ1+ TCM levels, and increased at the highest level around the pre-transplant levels of IL-12Rβ1+ TCM . However, the immunological advantage of Tac/MMF therapy was inhibited strongly by additive steroid administration. [ABSTRACT FROM AUTHOR]- Published
- 2016
- Full Text
- View/download PDF
31. Immunological potential of cytotoxic T lymphocyte antigen 4 immunoglobulin in murine autoimmune cholangitis.
- Author
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Tanaka, H., Yang, G‐X., Tomiyama, T., Tsuneyama, K., Zhang, W., Leung, P. S. C., Coppel, R. L., Joh, T., Nadler, S. G., Ansari, A. A., Bowlus, C., and Gershwin, M. E.
- Subjects
CYTOTOXIC T cells ,IMMUNOGLOBULINS ,AUTOIMMUNE diseases ,CHOLANGITIS ,IMMUNOLOGY ,LABORATORY mice ,DIAGNOSIS ,PATIENTS - Abstract
Cytotoxic T lymphocyte antigen 4 ( CTLA-4) immunoglobulin ( Ig) is an important regulator of T cell activation and a fusion protein directed at CD80 and CD86; it blocks co-stimulatory signalling and T cell activation. We have taken advantage of a murine model of human primary biliary cirrhosis ( PBC), mice expressing a transforming growth factor ( TGF)-β receptor II dominant negative ( dnTGF-β RII) transgene to address the potential therapeutic efficacy of CTLA-4 Ig. To mimic patients with PBC at different stages or duration of disease, we treated mice with either CTLA-4 Ig or control IgG three times weekly from 3 to 12 or 24 weeks of age, or from 12 to 24 weeks of age. CTLA-4 Ig treatment from 3 weeks of age significantly reduced liver inflammation to 12 weeks of age. Treatment initiated at 12 weeks of age also ameliorated the autoimmune cholangitis at 24 weeks of age. However, in mice treated at 3 weeks of age, suppression of liver inflammation was not sustained and colitis was aggravated when treatment was extended to 24 weeks of age. Our data indicate that, in dnTGF-βRII mice, CTLA-4 Ig treatment has short-term beneficial effects on autoimmune cholangitis, but the effect varies according to duration of treatment and the time in which therapy was initiated. Further dissection of the events that lead to the reduction in therapeutic effectiveness of CTLA-4 Ig will be critical to determining whether such efforts can be applied to human PBC. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
32. A distinct immunogenic region of glutamic acid decarboxylase 65 is naturally processed and presented by human islet cells to cytotoxic CD8 T cells.
- Author
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Knight, R. R., Dolton, G., Kronenberg‐Versteeg, D., Eichmann, M., Zhao, M., Huang, G. C., Beck, K., Cole, D. K., Sewell, A. K., Skowera, A., and Peakman, M.
- Subjects
GLUTAMATE decarboxylase ,ISLANDS of Langerhans ,CYTOTOXIC T cells ,AUTOANTIGENS ,CELL death ,TYPE 1 diabetes ,BIOMARKERS - Abstract
CD8 T cells specific for islet autoantigens are major effectors of β cell damage in type 1 diabetes, and measurement of their number and functional characteristics in blood represent potentially important disease biomarkers. CD8 T cell reactivity against glutamic acid decarboxylase 65 ( GAD65) in HLA- A*0201 subjects has been reported to focus on an immunogenic region 114-123 ( VMNILLQYVV), with studies demonstrating both 114-123 and 114-122 epitopes being targeted. However, the fine specificity of this response is unclear and the key question as to which epitope(s) β cells naturally process and present and, therefore, the pathogenic potential of CD8 T cells with different specificities within this region has not been addressed. We generated human leucocyte antigen ( HLA)- A*0201-restricted CD8 T cell clones recognizing either 114-122 alone or both 114-122 and 114-123. Both clone types show potent and comparable effector functions (cytokine and chemokine secretion) and killing of indicator target cells externally pulsed with cognate peptide. However, only clones recognizing 114-123 kill target cells transfected with HLA- A*0201 and GAD2 and HLA- A*0201
+ human islet cells. We conclude that the endogenous pathway of antigen processing by HLA- A*0201-expressing cells generates GAD65114-123 as the predominant epitope in this region. These studies highlight the importance of understanding β cell epitope presentation in the design of immune monitoring for potentially pathogenic CD8 T cells. [ABSTRACT FROM AUTHOR]- Published
- 2015
- Full Text
- View/download PDF
33. Cytotoxic and genotoxic responses of the RTgill-W1 fish cells in combination with the yeast oestrogen screen to determine the sediment quality of Lagos lagoon, Nigeria.
- Author
-
Amaeze, Nnamdi H., Schnell, Sabine, Sozeri, Osman, Otitoloju, Adebayo A., Egonmwan, Rosemary I., Arlt, Volker M., and Bury, Nic R.
- Subjects
GENETIC toxicology ,ESTROGEN ,ECOSYSTEMS ,RIVER sediment quality ,CYTOTOXIC T cells - Abstract
Economic advancements in developing countries have seen an increase in urbanisation and industrialisation with a rise in the levels of discharge of effluents and municipal waste into aquatic ecosystems. Unfortunately, aquatic environmental regulations in these countries are often rudimentary and the development of environmental monitoring programmes will help identify ecological risks. As an example, the current study assesses the pollution status of 11 sampling sites in Lagos lagoon, Nigeria. The organic solvent sediment extracts were assessed for cytotoxicity and genotoxicity in rainbow trout gill-W1 cells. The induction of oestrogenic activities using the yeast oestrogen screen was also determined. The sediments were analysed for polycyclic aromatic hydrocarbons (PAHs) and other contaminants (polychlorinated biphenyls, organochlorine and organophosphate pesticides). Only sediments from three sites were cytotoxic at both 25 and 12.5mg eQsed/ml using the Alamar Blue cell viability assay. The alkaline Comet assay showed that all sites caused significant DNA damage at 7mg eQsed/ml; the extent of the damage was site specific. The measure of oxidative damage to DNA via the formamidopyrimidine DNA-glycosylase-modified Comet assay revealed similar results. Toxicity to yeast cells was observed in extracts from six sites; of the remaining sites, only two exhibited oestrogenic activity. There was no strong consistent relationship between sediment PAH concentrations and the cell toxicity endpoints. The dynamic nature of Lagos lagoon with its tides and freshwater inputs are suggested as factors that make it difficult to link the sources of pollution observed at each site with PAH levels and toxic endpoints. The study has demonstrated that the Comet assay is a sensitive endpoint to identify sediments that possess genotoxic contaminants, and this in vitro bioassay has the potential to be incorporated into an environmental monitoring framework for Lagos lagoon. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
34. A mutation in X-linked inhibitor of apoptosis ( G466 X) leads to memory inflation of Epstein-Barr virus-specific T cells.
- Author
-
Lopez‐Granados, E., Stacey, M., Kienzler, A.‐K., Sierro, S., Willberg, C. B., Fox, C. P., Rigaud, S., Long, H. M., Hislop, A. D., Rickinson, A. B., Patel, S., Latour, S., Klenerman, P., and Chapel, H.
- Subjects
X-linked inhibitor of apoptosis protein ,EPSTEIN-Barr virus ,T cells ,GENE expression ,INTERFERONS - Abstract
Mutations in the X-linked inhibitor of apoptosis ( XIAP) gene have been associated with XLP-like disease, including recurrent Epstein-Barr virus ( EBV)-related haemophagocytic lymphohystiocytosis (HLH), but the immunopathogenic bases of EBV-related disease in XIAP deficiency is unknown. We present the first analysis of EBV-specific T cell responses in functional XIAP deficiency. In a family of patients with a novel mutation in XIAP ( G466 X) leading to a late-truncated protein and varying clinical features, we identified gradual hypogammaglobulinaemia and large expansions of T cell subsets, including a prominent CD4
+ CD8+ population. Extensive ex-vivo analyses showed that the expanded T cell subsets were dominated by EBV-specific cells with conserved cytotoxic, proliferative and interferon ( IFN)-γ secretion capacity. The EBV load in blood fluctuated and was occasionally very high, indicating that the XIAPG466X mutation could impact upon EBV latency. XIAP deficiency may unravel a new immunopathogenic mechanism in EBV-associated disease. [ABSTRACT FROM AUTHOR]- Published
- 2014
- Full Text
- View/download PDF
35. Enhancement of T cell recruitment and infiltration into tumours.
- Author
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Oelkrug, C. and Ramage, J. M.
- Subjects
CYTOTOXIC T cells ,CANCER immunotherapy ,CANCER cell migration ,T cell receptors ,NEOVASCULARIZATION ,CANCER patients - Abstract
Studies have documented that cancer patients with tumours which are highly infiltrated with cytotoxic T lymphocytes show enhanced survival rates. The ultimate goal of cancer immunotherapy is to elicit high-avidity tumour-specific T cells to migrate and kill malignant tumours. Novel antibody therapies such as ipilumimab (a cytotoxic T lymphocyte antigen-4 blocking antibody) show enhanced T cell infiltration into the tumour tissue and increased survival. More conventional therapies such as chemotherapy or anti-angiogenic therapy and recent therapies with oncolytic viruses have been shown to alter the tumour microenvironment and thereby lead to enhanced T cell infiltration. Understanding the mechanisms involved in the migration of high-avidity tumour-specific T cells into tumours will support and provide solutions for the optimization of therapeutic options in cancer immunotherapy. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
36. Allergy and Immunotoxicology in Occupational Health.
- Author
-
Fishwick, David
- Subjects
INDUSTRIAL hygiene ,IMMUNOTOXICOLOGY ,ALLERGIES ,CYTOTOXIC T cells ,OCCUPATIONAL medicine - Published
- 2020
- Full Text
- View/download PDF
37. Management of T-cell large granular lymphocyte leukemia and concurrent retroperitoneal liposarcoma.
- Subjects
T-cell lymphoma ,CYTOTOXIC T cells ,LIPOSARCOMA ,IMMUNOSUPPRESSIVE agents ,RADIOGRAPHY ,PATIENTS ,THERAPEUTICS - Abstract
T-cell large granular leukemia (T-LGL) is a rare lymphoproliferative disorder characterized by the clonal expansion of cytotoxic T lymphocytes. We present a unique case of T-LGL and concurrent retroperitoneal sarcoma occurring in a patient with long-standing rheumatoid arthritis. Pathology revealed a high-grade dedifferentiated liposarcoma. The diagnosis of T-LGL with a synchronous retroperitoneal sarcoma is a case that highlights the surgical management of these two rare conditions. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
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