102 results
Search Results
2. Response to Comment on Three X-ray Crystal Structure Papers.
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Salunke, Dinakar M., Khan, Tarique, Gaur, Vineet, Tapryal, Suman, and Kaur, Kanwaljeet
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CRYSTAL structure , *GERM cells - Abstract
A response from the authors of the articles on topics including X-ray crystal structures, Protein Data Bank (PDB) depositions, and structural analyses of germline is presented.
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- 2016
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3. Additional Comment on Three X-ray Crystal Structure Papers.
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Stanfield, Robyn, Pozharski, Edwin, and Rupp, Bernhard
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CRYSTAL structure , *ELECTRON density , *GERM cells - Abstract
A letter to the editor is presented in response to the articles focusing on X-ray crystal structure and mentions topics including pattern of electron density, Protein Data Bank (PDB) depositions, and structural analyses of germline.
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- 2016
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4. A Methods Paper That Led to Much More.
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Roopenian, Derry
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TRANSPLANTATION of organs, tissues, etc. , *HISTOCOMPATIBILITY - Abstract
An introduction is presented in which the editor discusses various reports within the issue on topics including genetics of tissue transplantation, histocompatibility genes, and histogenetic approaches developed by geneticist George Snell.
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- 2014
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5. Lack of Evidence for a Substantial Rate of Templated Mutagenesis in B Cell Diversification.
- Author
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Fukuyama, Julia, Olson, Branden J., and Matsen, Frederick A.
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B cells , *SOMATIC mutation , *IMMUNOGLOBULIN genes , *MUTAGENESIS , *GENOMES , *AGAMMAGLOBULINEMIA - Abstract
BCR sequences diversify through mutations introduced by purpose-built cellular machinery. A recent paper has concluded that a "templated mutagenesis" process is a major contributor to somatic hypermutation and therefore Ig diversification in mice and humans. In this proposed process, mutations in the Ig locus are introduced by copying short segments from other Ig genes. If true, this would overturn decades of research on B cell diversification and would require a complete rewrite of computational methods to analyze B cell data for these species. In this paper, we re-evaluate the templated mutagenesis hypothesis. By applying the original inferential method using potential donor templates absent from B cell genomes, we obtain estimates of the methods' false positive rates. We find false positive rates of templated mutagenesis in murine and human Ig loci that are similar to or even higher than the original rate inferences, and by considering the bases used in substitution, we find evidence that if templated mutagenesis occurs, it is at a low rate. We also show that the statistically significant results in the original paper can easily result from a slight misspecification of the null model. [ABSTRACT FROM AUTHOR]
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- 2020
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6. Effectiveness of interventions to reduce ordering of thyroid function tests: a systematic review.
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Zhelev, Zhivko, Abbott, Rebecca, Rogers, Morwenna, Hamilton, William Trevor, Heaton, Janet, Coon, Jo Thompson, Fleming, Simon, Patterson, Anthea, Vaidya, Bijay, and Hyde, Christopher
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THYROID gland function tests , *META-analysis , *PHYSICIAN practice patterns , *UTILIZATION review (Medical care) - Abstract
Objectives: To evaluate the effectiveness of behaviour changing interventions targeting ordering of thyroid function tests. Design: Systematic review. Data sources: MEDLINE, EMBASE and the Cochrane Database up to May 2015. Eligibility criteria for selecting studies: We included studies evaluating the effectiveness of behaviour change interventions aiming to reduce ordering of thyroid function tests. Randomised controlled trials (RCTs), non-randomised controlled studies and before and after studies were included. There were no language restrictions. Study appraisal and synthesis methods: 2 reviewers independently screened all records identified by the electronic searches and reviewed the full text of any deemed potentially relevant. Study details were extracted from the included papers and their methodological quality assessed independently using a validated tool. Disagreements were resolved through discussion and arbitration by a third reviewer. Metaanalysis was not used. Results: 27 studies (28 papers) were included. They evaluated a range of interventions including guidelines/protocols, changes to funding policy, education, decision aids, reminders and audit/feedback; often intervention types were combined. The most common outcome measured was the rate of test ordering, but the effect on appropriateness, test ordering patterns and cost were also measured. 4 studies were RCTs. The majority of the studies were of poor or moderate methodological quality. The interventions were variable and poorly reported. Only 4 studies reported unsuccessful interventions but there was no clear pattern to link effect and intervention type or other characteristics. Conclusions: The results suggest that behaviour change interventions are effective particularly in reducing the volume of thyroid function tests. However, due to the poor methodological quality and reporting of the studies, the likely presence of publication bias and the questionable relevance of some interventions to current day practice, we are unable to draw strong conclusions or recommend the implementation of specific intervention types. Further research is thus justified. [ABSTRACT FROM AUTHOR]
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- 2019
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7. Chaperone-Mediated Autophagy Suppresses Apoptosis via Regulation of the Unfolded Protein Response during Chronic Obstructive Pulmonary Disease Pathogenesis.
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Yusuke Hosaka, Jun Araya, Yu Fujita, Tsukasa Kadota, Kazuya Tsubouchi, Masahiro Yoshida, Shunsuke Minagawa, Hiromichi Hara, Hironori Kawamoto, Naoaki Watanabe, Akihiko Ito, Akihiro Ichikawa, Nayuta Saito, Keitaro Okuda, Junko Watanabe, Daisuke Takekoshi, Hirofumi Utsumi, Mitsuo Hashimoto, Hiroshi Wakui, and Saburo Ito
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UNFOLDED protein response , *CHRONIC obstructive pulmonary disease , *GLYCOGEN storage disease type II , *AUTOPHAGY , *METHACHOLINE chloride , *PULMONARY function tests , *PROTEOLYSIS - Abstract
Cigarette smoke (CS) induces accumulation of misfolded proteins with concomitantly enhanced unfolded protein response (UPR). Increased apoptosis linked to UPR has been demonstrated in chronic obstructive pulmonary disease (COPD) pathogenesis. Chaperone-mediated autophagy (CMA) is a type of selective autophagy for lysosomal degradation of proteins with the KFERQ peptide motif. CMA has been implicated in not only maintaining nutritional homeostasis but also adapting the cell to stressed conditions. Although recent papers have shown functional cross-talk between UPRand CMA, mechanistic implications for CMA in COPD pathogenesis, especially in association with CS-evoked UPR, remain obscure. In this study, we sought to examine the role of CMA in regulating CS-induced apoptosis linked to UPR during COPD pathogenesis using human bronchial epithelial cells (HBEC) and lung tissues. CS extract (CSE) induced LAMP2A expression and CMA activation through a Nrf2-dependent manner in HBEC. LAMP2A knockdown and the subsequent CMA inhibition enhanced UPR, including CHOP expression, and was accompanied by increased apoptosis during CSE exposure, which was reversed by LAMP2A overexpression. Immunohistochemistry showed that Nrf2 and LAMP2A levels were reduced in small airway epithelial cells in COPD compared with non-COPD lungs. Both Nrf2 and LAMP2A levels were significantly reduced in HBEC isolated from COPD, whereas LAMP2A levels in HBEC were positively correlated with pulmonary function tests. These findings suggest the existence of functional cross-talk between CMA and UPR during CSE exposure and also that impaired CMA may be causally associated with COPD pathogenesis through enhanced UPR-mediated apoptosis in epithelial cells. [ABSTRACT FROM AUTHOR]
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- 2020
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8. The Quantitative Assessment of the Secreted IgG Repertoire after Recall to Evaluate the Quality of Immunizations.
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Eyer, Klaus, Castrillon, Carlos, Chenon, Guilhem, Bibette, Jérôme, Bruhns, Pierre, Griffiths, Andrew D., and Baudry, Jean
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IMMUNIZATION , *SPLEEN , *VACCINATION , *TITERS , *PHENOTYPES - Abstract
One of the major goals of vaccination is to prepare the body to rapidly secrete specific Abs during an infection. Assessment of the vaccine quality is often difficult to perform, as simple measurements like Ab titer only partly correlate with protection. Similarly, these simple measurements are not always sensitive to changes in the preceding immunization scheme. Therefore, we introduce in this paper a new, to our knowledge, method to assay the quality of immunization schemes for mice: shortly after a recall with pure Ag, we analyze the frequencies of IgG-secreting cells (IgG-SCs) in the spleen, as well as for each cells, the Ag affinity of the secreted Abs. We observed that after recall, appearance of the IgG-SCs within the spleen of immunized mice was fast (<24 h) and this early response was free of naive IgG-SCs. We further confirmed that our phenotypic analysis of IgG-SCs after recall strongly correlated with the different employed immunization schemes. Additionally, a phenotypic comparison of IgG-SCs presented in the spleen during immunization or after recall revealed similarities but also significant differences. The developed approach introduced a novel (to our knowledge), quantitative, and functional highly resolved alternative to study the quality of immunizations. [ABSTRACT FROM AUTHOR]
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- 2020
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9. A Novel Utility to Correct for Plate/Batch/Lot and Nonspecific Binding Artifacts in Luminex Data.
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Maecker, Holden T., Rosenberg-Hasson, Yael, Kolstad, Kathleen Durgin, Steen, Virginia D., and Chung, Lorinda S.
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NONLINEAR regression , *SYSTEMIC scleroderma , *CONTROL boards (Electrical engineering) , *NONLINEAR functions , *FLUORESCENCE - Abstract
Cytokines and other secreted soluble proteins are routinely assayed as fluorescence intensities on the Luminex (Luminex, Austin, TX) platform. As with any immunoassay, a portion of the measured Ab binding can be nonspecific. Use of spiked-in microbead controls (e.g., AssayChex Process, Control Panel; Radix Biosolutions, Georgetown, TX) can determine the level of nonspecific binding on a per specimen basis. A statistical approach for correction of this assay's nonspecific binding artifact was first described in earlier work. The current paper describes a novel utility written in the R language (https://www.r-project.org), that refines correction for nonspecific binding in three important ways: 1) via local polynomial regression, the utility allows for curvature in relationships between soluble protein median fluorescence intensities and nonspecific binding median fluorescence intensities; 2) to stabilize correction, the fit of the nonlinear regression function is obtained via repeated cross-validation; and 3) the utility addresses possible bias due to technical error in measured nonspecific binding. The utility first logarithm transforms and then removes plate/batch/lot artifacts from median fluorescence intensities prior to correction for nonspecific binding, even when plates/batches/lots are unbalanced with respect to experimental factors of interest. Continuous (e.g., age) and categorical (e.g., diagnosis) covariates are accommodated in plate/batch/lot artifact correction. We present application of the utility to a panel of 62 cytokines in a sample of human patients diagnosed with systemic sclerosis and to an experiment that examined multiple lots of a human 51-cytokine panel. The R script for our new utility is publicly available for download from the web. [ABSTRACT FROM AUTHOR]
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- 2020
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10. Low-Dose IL-2 Therapy in Transplantation, Autoimmunity, and Inflammatory Diseases.
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Tahvildari, Maryam and Dana, Reza
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SUPPRESSOR cells , *SYSTEMIC lupus erythematosus , *AUTOIMMUNITY , *TYPE 1 diabetes , *HEPATITIS C , *EYE drops - Abstract
Regulatory T cells (Tregs) play a central role in the induction and maintenance of immune homeostasis and self-tolerance. Tregs constantly express the high-affinity receptor to IL-2. IL-2 is a pleiotropic cytokine and a key survival factor for Tregs. It maintains Tregs' suppressive function by promoting Foxp3 expression and subsequent production of immunoregulatory cytokines. Administration of low-dose IL-2 is shown to be a promising approach to prevent allograft rejection and to treat autoimmune and inflammatory conditions in experimental models. The combination of IL-2 with its mAb (JES6-1) has also been shown to increase the t1/2 of IL-2 and further enhance Treg frequencies and function. Low-dose IL-2 therapy has been used in several clinical trials to treat conditions such as hepatitis C vasculitis, graft-versus-host disease, type 1 diabetes, and systemic lupus erythematosus. In this paper, we summarize our findings on low-dose IL-2 treatment in corneal allografting and review recent studies focusing on the use of low-dose IL-2 in transplantation, autoimmunity, and other inflammatory conditions. We also discuss potential areas of further investigation with the aim to optimize current low-dose IL-2 regimens. [ABSTRACT FROM AUTHOR]
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- 2019
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11. KIR3DL1/S1 Allotypes Contribute Differentially to the Development of Behçet Disease.
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Petrushkin, Harry, Norman, Paul J., Lougee, Emma, Parham, Peter, Wallace, Graham R., Stanford, Miles R., and Fortune, Farida
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ODDS ratio , *CHRONIC diseases , *CONFIDENCE intervals , *DISEASES - Abstract
Behçet disease is a chronic, relapsing-remitting autoinflammatory syndrome with a strong HLA-B*51 association. In this paper, we describe a human cohort of 267 individuals with Behçet disease and 445 matched controls from a tertiary referral center in the U.K. HLA-B*51 was confirmed as a genetic risk factor in this group (p = 0.0006, Bonferroni-Dunn correction for multiple testing [Pc] = 0.0192, odds ratio [OR] 1.92, 95% confidence interval [CI] 1.33-2.76). KIR3DL1/S1 allele-level analysis indicated that low-expressing KIR3DL1/S1 alleles in combination with KIR3DS1 increased the risk of developing Behçet disease (KIR3DL1LOW/KIR3DS1: p = 0.0004, Pc = 0.0040, OR 2.47, 95% CI 1.43-4.25), whereas high-expressing KIR3DL1/S1 alleles in combination with a null-expressing KIR3DL1 reduced the risk of disease (KIR3DL1HIGH/KIR3DL1NULL: p = 0.0035, Pc = 0.0350, OR 0.53, 95% CI 0.33-0.87). Behçet disease can manifest as a purely mucocutaneous disease or can involve other organ systems such as the eyes. In the U.K. cohort studied in this study, KIR3DL1LOW/KIR3DS1 increased the risk of ophthalmic disease (p = 1.2 × 10-5, OR 3.92, 95% CI 2.06-7.47), whereas KIR3DL1HIGH/KIR3DL1NULL reduced the risk of having purely mucocutaneous disease (p = 0.0048, OR 0.45, 95% CI 0.25-0.81). To our knowledge, this is the first analysis of KIR3DL1/S1 allelic variation in Behçet disease and may provide insight into the pathogenic role of HLA-B*51 and its interaction with KIR3DL1/S1. [ABSTRACT FROM AUTHOR]
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- 2019
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12. IL-6 Signaling Blockade during CD40-Mediated Immune Activation Favors Antitumor Factors by Reducing TGF-β, Collagen Type I, and PD-L1/PD-1.
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Eriksson, Emma, Milenova, Ioanna, Wenthe, Jessica, Moreno, Rafael, Alemany, Ramon, and Loskog, Angelica
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CANCER cell differentiation , *CANCER cells - Abstract
IL-6 plays a role in cancer pathogenesis via its connection to proteins involved in the formation of desmoplastic stroma and to immunosuppression by driving differentiation of myeloid suppressor cells together with TGF-β. Inhibition of IL-6 signaling in the tumor microenvironment may, thus, limit desmoplasia and myeloid suppressor cell differentiation. CD40 signaling can further revert myeloid cell differentiation toward antitumor active phenotypes. Hence, the simultaneous use of IL-6 blockade with CD40 stimuli may tilt the tumor microenvironment to promote antitumor immune responses. In this paper, we evaluated the mechanisms of LOAd713, an oncolytic adenovirus designed to block IL-6R signaling and to provide myeloid cell activation via a trimerized membrane-bound isoleucine zipper (TMZ) CD40L. LOAd713-infected pancreatic cancer cells were killed by oncolysis, whereas infection of stellate cells reduced factors involved in stroma formation, including TGF-β-1 and collagen type I. Virus infection prevented IL-6/GM-CSF-mediated differentiation of myeloid suppressors, but not CD163 macrophages, whereas infection of dendritic cells led to upregulation of maturation markers, including CD83, CD86, IL-12p70, and IFN-γ. Further, IL-6R blockade prevented upregulation of programed death ligand 1 (PD-L1) and PD-1 on the stimulated dendritic cells. These results suggest that LOAd713 can kill infected tumor cells and has the capacity to affect the tumor microenvironment by stimulating stellate cells and myeloid suppressors with TMZ-CD40L and IL-6R blockade. Gene transfer of murine TMZ-CD40L prolonged survival in an animal model. LOAd713 may be an interesting therapeutic option for cancers connected to IL-6 signaling, such as pancreatic cancer. [ABSTRACT FROM AUTHOR]
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- 2019
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13. B Cell ADAM10 Controls Murine Lupus Progression through Regulation of the ICOS:ICOS Ligand Axis.
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Lownik, Joseph C., Wimberly, Jessica L., Conrad, Daniel H., and Martin, Rebecca K.
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B cells - Abstract
The role of ICOS and its ligand (ICOSL) have both been shown to be essential for proper humoral responses as well as autoimmune Ab development in mouse models of lupus. In this paper, we report a specific role for the metalloprotease ADAM10 on B cells in regulating both ICOSL and ICOS in a mouse model of increased humoral immunity using B6mir146a-/- mice and a model of lymphoproliferative disease using the well-characterized lpr model. B6lpr mice lacking ADAM10 on B cells (A10Blpr) have decreased nodal proliferation and T cell accumulation compared with control B6lpr mice. Additionally, A10Blpr mice have a drastic reduction in autoimmune anti-dsDNA Ab production. In line with this, we found a significant reduction in follicular helper T cells and germinal center B cells in these mice. We also show that lymphoproliferation in this model is closely tied to elevated ICOS levels and decreased ICOSL levels. Overall, our data not only show a role of B cell ADAM10 in control autoimmunity but also increase our understanding of the regulation of ICOS and ICOSL in the context of autoimmunity. [ABSTRACT FROM AUTHOR]
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- 2019
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14. Induction of a Long Noncoding RNA Transcript, NR_045064, Promotes Defense Gene Transcription and Facilitates Intestinal Epithelial Cell Responses against Cryptosporidium Infection.
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Min Li, Ai-Yu Gong, Xin-Tian Zhang, Yang Wang, Mathy, Nicholas W., Xian-Ming Chen, Martins, Gislaine A., and Strauss-Soukup, Juliane K.
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Cryptosporidium is an important opportunistic intestinal pathogen for immunocompromised individuals and a common cause of diarrhea in young children in developing countries. Gastrointestinal epithelial cells play a central role in activating and orchestrating host immune responses against Cryptosporidium infection, but underlying molecular mechanisms are not fully understood. We report in this paper that C. parvum infection causes significant alterations in long noncoding RNA (lncRNA) expression profiles in murine intestinal epithelial cells. Transcription of a panel of lncRNA genes, including NR_045064, in infected cells is controlled by the NF-kB signaling. Functionally, inhibition of NR_045064 induction increases parasite burden in intestinal epithelial cells. Induction of NR_045064 enhances the transcription of selected defense genes in host cells following C. parvum infection. Epigenetic histone modifications are involved in NR_045064-mediated transcription of associated defense genes in infected host cells. Moreover, the p300/MLL-associated chromatin remodeling is involved in NR_045064-mediated transcription of associated defense genes in intestinal epithelial cells following C. parvum infection. Expression of NR_045064 and associated genes is also identified in intestinal epithelium in C57BL/6J mice following phosphorothioate oligodeoxynucleotide or LPS stimulation. Our data demonstrate that lncRNAs, such as NR_045064, play a role in regulating epithelial defense against microbial infection. [ABSTRACT FROM AUTHOR]
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- 2018
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15. Programming of CD8 T Cell Quantity and Polyfunctionality by Direct IL-1 Signals.
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Kalia, Vandana, Sarkar, Surojit, Hanxi Xiao, Yuzefpolskiy, Yevgeniy, Baumann, Florian M., Soojin Yim, Lee, David J., and Schenten, Dominik
- Abstract
IL-1, generally considered an amplifier of adaptive immune responses, has been proposed for use as adjuvant during immunization with weak immunogens. However, its effects on memory T cell function remain largely undefined. Using the murine model of acute viral infection, in this paper, we show that in addition to augmenting the size of the Ag-specific pool, IL-1 signals act directly on CD8 T cells to promote the quality of effector and memory responses. Ablation of IL-1R1 or MyD88 signaling in T cells led to functional impairment; both the ability to produce multiple cytokines on a per cell basis (polyfunctionality) and the potential for recall proliferation in response to antigenic restimulation were compromised. IL-1 supplementation during priming augmented the expansion of Ag-specific CD8 T cells through the MyD88-IRAK1/4 axis, resulting in a larger memory pool capable of robust secondary expansion in response to rechallange. Together, these findings demonstrate a critical role of the IL-1-MyD88 axis in programming the quantity and quality of memory CD8 T cell responses and support the notion that IL-1 supplementation may be exploited to enhance adoptive T cell therapies against cancers and chronic infections. [ABSTRACT FROM AUTHOR]
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- 2018
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16. The Diverse Family of MR1-Restricted T Cells.
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Gherardin, Nicholas A., McCluskey, James, and Godfrey, Dale I.
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T cells , *LYMPHOCYTES , *CD4 antigen , *ANTIBIOTICS , *HETEROGENEITY - Abstract
Mucosal-associated invariant T (MAIT) cells are characterized by a semi-invariant TCR that recognizes vitamin B metabolite Ags presented by the MHC-related molecule MR1. Their Ag restriction determines a unique developmental lineage, imbuing a tissue-homing, preprimed phenotype with antimicrobial function. A growing body of literature indicates that MR1-restricted T cells are more diverse than the MAIT term implies. Namely, it is increasingly clear that TCR a- and TCR b-chain diversity within the MR1-restricted repertoire provides a potential mechanism of Ag discrimination, and context-dependent functional variation suggests a role for MR1-restricted T cells in diverse physiological settings. In this paper, we summarize MR1-restricted T cell biology, with an emphasis on TCR diversity, Ag discrimination, and functional heterogeneity. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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17. Oxidant Signaling Mediated by Nox2 in Neutrophils Promotes Regenerative Myelopoiesis and Tissue Recovery following Ischemic Damage.
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Fang, Milie M., Barman, Pijus K., Thiruppathi, Muthusamy, Mirza, Rita E., Koh, Timothy J., Norifumi Urao, McKinney, Ronald D., Xiaoping Du, Jing Deng, Christman, John W., Fukai, Tohru, Ennis, William J., and Masuko Ushio-Fukai
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NEUTROPHILS , *HEMATOPOIETIC stem cells , *BONE marrow , *HYDROGEN peroxide , *PHOSPHOLIPIDS - Abstract
Ischemic tissue damage activates hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM)-generating myeloid cells, and persistent HSPC activity may drive chronic inflammation and impair tissue recovery. Although increased reactive oxygen species in the BM regulate HSPC functions, their roles in myelopoiesis of activated HSPCs and subsequent tissue recovery during ischemic damage are not well understood. In this paper, we report that deletion of Nox2 NADPH oxidase in mice results in persistent elevations in BM HSPC activity and levels of inflammatory monocytes/macrophages in BM and ischemic tissue in a model of hindlimb ischemia. Ischemic tissue damage induces oxidants in BM such as elevations of hydrogen peroxide and oxidized phospholipids, which activate redox-sensitive Lyn kinase in a Nox2-dependent manner. Moreover, during tissue recovery after ischemic injury, this Nox2-ROS--Lyn kinase axis is induced by Nox2 in neutrophils that home to the BM, which inhibits HSPC activity and inflammatory monocyte generation and promotes tissue regeneration after ischemic damage. Thus, oxidant signaling in the BM mediated by Nox2 in neutrophils regulates myelopoiesis of HSPCs to promote regeneration of damaged tissue. [ABSTRACT FROM AUTHOR]
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- 2018
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18. The Role of WNT Signaling in Mature T Cells: T Cell Factor Is Coming Home.
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van Loosdregt, Jorg and Coffer, Paul J.
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T cells , *TRANSCRIPTION factors , *HEMATOPOIESIS , *IMMUNOLOGY , *STEM cells , *CATENINS - Abstract
T cell factor, the effector transcription factor of the WNT signaling pathway, was so named because of the primary observation that it is indispensable for T cell development in the thymus. Since this discovery, the role of this signaling pathway has been extensively studied in T cell development, hematopoiesis, and stem cells; however, its functional role in mature T cells has remained relatively underinvestigated. Over the last few years, various studies have demonstrated that T cell factor can directly influence T cell function and the differentiation of Th1, Th2, Th17, regulatory T cell, follicular helper CD4+ T cell subsets, and CD8+ memory T cells. In this paper, we discuss the molecular mechanisms underlying these observations and place them in the general context of immune responses. Furthermore, we explore the implications and limitations of these findings for WNT manipulation as a therapeutic approach for treating immune-related diseases. [ABSTRACT FROM AUTHOR]
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- 2018
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19. Syndecan-1 Regulates Psoriasiform Dermatitis by Controlling Homeostasis of IL-17-Producing γδ T Cells.
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Jaiswal, Anil Kumar, Sadasivam, Mohanraj, Archer, Nathan K., Miller, Robert J., Dillen, Carly A., Ravipati, Advaitaa, Park, Pyong Woo, Chakravarti, Shukti, Miller, Lloyd S., and Hamad, Abdel Rahim A.
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SKIN inflammation , *SYNDECANS , *T cells , *HOMEOSTASIS , *APOPTOSIS - Abstract
IL-17 is a potent proinflammatory cytokine that drives pathogenesis of multiple autoimmune diseases, including psoriasis. A major source of pathogenic IL-17 is a subset of γδ T cells (Tγδ17) that acquires the ability to produce IL-17 while developing in the thymus. The mechanisms that regulate homeostasis of Tγδ17 cells and their roles in psoriasis, however, are not fully understood. In this paper, we show that the heparan sulfate proteoglycan syndecan-1 (sdc1) plays a critical role in regulating homeostasis of Tγδ17 cells and modulating psoriasis-like skin inflammation in mice. sdc1 was predominantly expressed by Tγδ17 cells (but not IL-172 Tγδ cells) in the thymus, lymph nodes, and dermis. sdc1 deficiency significantly and selectively increased the frequency and absolute numbers of Tγδ17 cells by mechanisms that included increased proliferation and decreased apoptosis. Adoptive transfer experiments ruled out a significant role of sdc1 expressed on nonhematopoietic cells in halting expansion and proliferation of sdc1-deficient Tγδ17 cells. When subjected to imiquimod-induced psoriasiform dermatitis, Tγδ17 cells in sdc1KO mice displayed heightened responses accompanied by significantly increased skin inflammation than their wild-type counterparts. Furthermore, transferred sdc1-deficient γδ T cells caused more severe psoriasiform dermatitis than their sdc1-sufficient counterparts in TCR-β δ KO hosts. The results uncover a novel role for sdc1 in controlling homeostasis of Tγδ17 cells and moderating host responses to psoriasis-like inflammation. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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20. CD4+ Regulatory T Cells Exert Differential Functions during Early and Late Stages of the Immune Response to Respiratory Viruses.
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Shafagati, Nazly, Johnson, Monika, Williams, John V., Rogers, Meredith C., Lamens, Kristina D., Joyce, Sebastian, and Oury, Tim D.
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ADULT respiratory distress syndrome , *T cells , *CYTOKINES , *MICE , *PHENOTYPES - Abstract
Acute respiratory virus infection (ARI) induces CD8+ T cells with diminished cytokine production and functional impairment. The role of cellular mediators of immune impairment, specifically CD4+ regulatory T cells (Tregs), is incompletely understood in ARI. Tregs are known suppressors of effector T cell function, but whether they are detrimental or beneficial in ARI remains controversial. We show in this paper that Treg depletion leads to increased CD8+ T cell function and lower virus titer in mice infected with human metapneumovirus. We further demonstrate that Tregs play a temporal role in the immune response to human metapneumovirus and influenza: Treg depletion before infection pathologically reduces virus-specific CD8+ T cell numbers and delays virus clearance, whereas depletion 2 d postinoculation enhances CD8+ T cell functionality without reducing virus-specific CD8+ T cell numbers. Mechanistically, Treg depletion during immune priming led to impaired dendritic cell and CD8+ T cell migration. Further, early Treg depletion was associated with immune skewing toward a type 2 phenotype characterized by increased type 2 innate lymphoid cells and TH2 CD4+ T cells, which was not observed when Treg depletion was delayed until after inoculation. These results indicate that the presence of Tregs at inoculation is critical for efficient priming of the CD8+ T cell response to ARI, whereas later in infection, Tregs are dispensable for virus clearance. [ABSTRACT FROM AUTHOR]
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- 2018
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21. Rhabdovirus-Inducible MicroRNA-210 Modulates Antiviral Innate Immune Response via Targeting STING/MITA in Fish.
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Qing Chu, Tianjun Xu, and Junxia Cui
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RHABDOVIRUSES , *MICRORNA , *FISH genetics , *ENZYME inhibitors , *PLASMIDS - Abstract
Viral infection induces type I IFN production, which plays critical roles in orchestrating the antiviral defense by inducing direct antiviral activities. To establish a persistent infection, viruses have evolved numerous strategies to specifically interfere with IFN production or its downstream mediators, thereby evading the immune responses. MicroRNAs (miRNAs) are a family of small non-coding RNAs that posttranscriptionally regulate the expressions of specific target genes. Although accumulating evidence demonstrates that miRNAs play vital roles in regulating viral infection, miRNAs that target intracellular sensors and adaptors of innate immunity have not been fully uncovered. In this paper, we identify fish miR-210 as a robust regulator involved in regulating virus--host interactions. We found that rhabdovirus significantly upregulated the expression of fish miR-210. Inducible miR-210 modulates virus-triggered type I IFN and inflammatory cytokine production by targeting stimulator of IFN genes (STING), thereby promoting viral replication. Furthermore, we demonstrated that miR-210 regulates innate immune response through NF-κB, IFN regulatory factor 3, and JAK/STAT signaling pathways. The collective findings indicate that inducible miR-210 plays a regulatory role in virus--host interactions through STING-mediated singling pathway by targeting STING. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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22. The Hayflick Limit May Determine the Effective Clonal Diversity of Naive T Cells.
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Ndifon, Wilfred and Dushoff, Jonathan
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T cells , *CD4 antigen , *CD8 antigen , *CELL proliferation , *HOMEOSTASIS - Abstract
Having a large number of sufficiently abundant T cell clones is important for adequate protection against diseases. However, as shown in this paper and elsewhere, between young adulthood and >70 y of age the effective clonal diversity of naive CD4/CD8 T cells found in human blood declines by a factor of >10. (Effective clonal diversity accounts for both the number and the abundance of T cell clones.) The causes of this observation are incompletely understood. A previous study proposed that it might result from the emergence of certain rare, replication-enhancing mutations in T cells. In this paper, we propose an even simpler explanation: that it results from the loss of T cells that have attained replicative senescence (i.e., the Hayflick limit). Stochastic numerical simulations of naive T cell population dynamics, based on experimental parameters, show that the rate of homeostatic T cell proliferation increases after the age of ~60 y because naive T cells collectively approach replicative senescence. This leads to a sharp decline of effective clonal diversity after ~70 y, in agreement with empirical data. A mathematical analysis predicts that, without an increase in the naive T cell proliferation rate, this decline will occur >50 yr later than empirically observed. These results are consistent with a model in which exhaustion of the proliferative capacity of naive T cells causes a sharp decline of their effective clonal diversity and imply that therapeutic potentiation of thymopoiesis might either prevent or reverse this outcome. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
23. Response to Additional Comment on Three X-ray Crystal Structure Papers.
- Author
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Salunke, Dinakar M., Khan, Tarique, Gaur, Vineet, Tapryal, Suman, and Kaur, Kanwaljeet
- Subjects
- *
CRYSTAL structure , *X-ray crystallography - Abstract
A letter to the editor is presented in response to the article regarding x-ray crystal structure.
- Published
- 2016
- Full Text
- View/download PDF
24. Passive Serum Therapy to Immunomodulation by IVIG: A Fascinating Journey of Antibodies.
- Author
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João, Cristina, Negi, Vir Singh, Kazatchkine, Michel D., Bayry, Jagadeesh, and Kaveri, Srini V.
- Subjects
- *
IMMUNOLOGICAL adjuvants , *INTRAVENOUS immunoglobulins , *SEROTHERAPY , *GLOBULINS , *METAMORPHOSIS - Abstract
The immunoregulatory and anti-infective properties of normal circulating polyclonal Abs have been exploited for the therapeutic purposes in the form of IVIG as well as several hyperimmune globulins. Current knowledge on the therapeutic use of normal Igs is based on the discoveries made by several pioneers of the field. In this paper, we review the evolution of IVIG over the years. More importantly, the process started as an s.c. replacement in g globulin-deficient patients, underwent metamorphosis into i.m. Ig, was followed by IVIG, and is now back to s.c. forms. Following successful use of IVIG in immune thrombocytopenic purpura, there has been an explosion in the therapeutic applications of IVIG in diverse autoimmune and inflammatory conditions. In addition to clinically approved pathological conditions, IVIG has been used as an off-label drug in more than 100 different indications. The current worldwide consumption of IVIG is over 100 tons per year. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
25. Human and Rhesus Macaque KIR Haplotypes Defined by Their Transcriptomes.
- Author
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Bruijnesteijn, Jesse, van der Wiel, Marit K. H., Otting, Nel, Doxiadis, Gaby G., De Groot, Natasja G., Bontrop, Ronald E., Swelsen, Wendy T. N., de Vos-Rouweler, Annemiek J. M., Lardy, Neubury M., Elferink, Diënne, and Claas, Frans H. J.
- Subjects
- *
KILLER cells , *IMMUNOGLOBULIN receptors , *IMMUNE recognition , *T cells , *RHESUS monkeys , *PYROSEQUENCING - Abstract
The killer-cell Ig-like receptors (KIRs) play a central role in the immune recognition in infection, pregnancy and transplantation through their interactions with MHC class I molecules. KIR genes display abundant copy number variation as well as high levels of polymorphism. As a result, it is challenging to characterize this structurally dynamic region. KIR haplotypes have been analyzed in different species using conventional characterization methods, such as Sanger sequencing and Roche/454 pyrosequencing. However, these methods are time-consuming and often failed to define complete haplotypes, or do not reach allele-level resolution. In addition, most analyses were performed on genomic DNA and thus were lacking substantial information about transcription and its corresponding modifications. In this paper, we present a single-molecule real-time sequencing approach, using Pacific Biosciences Sequel platform to characterize the KIR transcriptomes in human and rhesus macaque (Macaca mulatta) families. This high-resolution approach allowed the identification of novel Mamu-KIR alleles, the extension of reported allele sequences and the determination of human and macaque KIR haplotypes. In addition, multiple recombinant KIR genes were discovered, all located on contracted haplotypes, which were likely the result of chromosomal rearrangements. The relatively high number of contracted haplotypes discovered might be indicative of selection on small KIR repertoires and/or novel fusion gene products. This next-generation method provides an improved high-resolution characterization of the KIR cluster in humans and macaques, which eventually may aid in a better understanding and interpretation of KIR allele-associated diseases, as well as the immune response in transplantation and reproduction. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
26. Critical Role of IL-22/IL22-RA1 Signaling in Pneumococcal Pneumonia.
- Author
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Trevejo-Nunez, Giraldina, Elsegeiny, Waleed, Conboy, Parker, Kong Chen, and Kolls, Jay K.
- Subjects
- *
EXTRACELLULAR space , *PATHOGENIC microorganisms , *LABORATORY mice , *PNEUMOCOCCAL pneumonia , *PREVENTION , *PATIENTS - Abstract
IL-22-IL-22R signaling plays a crucial role in regulating host defenses against extracellular pathogens, particularly in the intestine, through the induction of antimicrobial peptides and chemotactic genes. However, the role of IL-22-IL-22R is understudied in Streptococcus pneumoniae lung infection, a prevalent pathogen of pneumonia. This paper presents the findings of IL-22 signaling during a murine model of pneumococcal pneumonia and improvement of bacterial burden upon IL-22 administration. IL-22 was rapidly induced in the lung during pneumococcal infection in wild-type mice, and Il22-/- mice had higher pneumococcal burdens compared with controls. Additionally, mice with hepatic-specific deletion of Il22ra1 also had higher bacterial burdens in lungs compared with littermate controls after intrapulmonary pneumococcal infection, suggesting that IL-22 signaling in the liver is important to control pneumococcal pneumonia. Thus, we hypothesized that enhancement of IL-22 signaling would control pneumococcal burden in lung tissues in an experimental pneumonia model. Administration of rIL-22 systemically to infected wild-type mice decreased bacterial burden in lung and liver at 24 h postinfection. Our in vitro studies also showed that mice treated with IL-22 had increased C3 expression in the liver compared with the isotype control group. Furthermore, serum from mice treated with IL-22 had improved opsonic capacity by increasing C3 binding on S. pneumoniae. Taken together, endogenous IL-22 and hepatic IL-22R signaling play critical roles in controlling pneumococcal lung burden, and systemic IL-22 decreases bacterial burden in the lungs and peripheral organs by potentiating C3 opsonization on bacterial surfaces, through the increase of hepatic C3 expression. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
27. MicroRNA-155 Is Essential for the T Cell-Mediated Control of Helicobacter pylori Infection and for the Induction of Chronic Gastritis and Colitis.
- Author
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Oertli, Mathias, Engler, Daniela B., Kohler, Esther, Koch, Manuel, Meyer, Thomas F., and Müller, Anne
- Subjects
- *
IMMUNE response , *ALLERGENS , *AUTOANTIBODIES , *T cells , *HELICOBACTER pylori infections , *GASTRITIS , *COLITIS - Abstract
MicroRNAs govern immune responses to infectious agents, allergens, and autoantigens and function by posttranscriptional repression of their target genes. In this paper, we have addressed the role of microRNA-155 (miR-155) in the control of Helicobacter pylori infection of the gastrointestinal tract and the development of H. pylori-induced chronic gastritis and associated gastric preneoplastic pathology. We show that miR-155 is upregulated in the gastric mucosa of experimentally infected mice and that miR-155-/- mice fail to control H. pylori infection as a result of impaired pathogen-specific Th1 and Th17 responses. miR-155-/- mice are also less well protected against challenge infection after H. pylori-specific vaccination than their wild-type (wt) counterparts. As a consequence of their impaired T cell responses to H. pylori, miR-155-/- mice develop less severe infection-induced immunopathology manifesting as chronic atrophic gastritis, epithelial hyperplasia, and intestinal metaplasia. T cells from miR-155-/- mice that are activated by CD3/CD28 cross-linking expand less and produce less IFN-γ and IL-17 than wt T cells. Finally, we show in this paper using adoptive transfers that the phenotypes of miR-155-/- mice are likely due to T cell-intrinsic defects. In contrast to wt T cells, miR-155-/- T cells from infected donors do not control H. pylori infections in T cell-deficient recipients, do not differentiate into Th1 or Th17 cells, and do not cause immunopathology. In addition, naive miR-155-/- T cells fail to induce chronic Th17-driven colitis in an adoptive transfer model. In conclusion, miR-155 expression is required for the Th17/Th1 differentiation that underlies immunity to H. pylori infection on the one hand and infection-associated immunopathology on the other. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
28. STAT3 Impairs STAT5 Activation in the Development of IL-9-Secreting T Cells.
- Author
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Olson, Matthew R., Verdan, Felipe Fortino, Hufford, Matthew M., Dent, Alexander L., and Kaplan, Mark H.
- Subjects
- *
STAT proteins , *T cells , *INTERLEUKIN-9 , *TRANSCRIPTION factors , *CELLULAR signal transduction , *PHYSIOLOGY - Abstract
Th cell subsets develop in response to multiple activating signals, including the cytokine environment. IL-9-secreting T cells develop in response to the combination of IL-4 and TGF-β, although they clearly require other cytokine signals, leading to the activation of transcription factors including STAT5. In Th17 cells, there is a molecular antagonism of STAT5 with STAT3 signaling, although whether this paradigm exists in other Th subsets is not clear. In this paper, we demonstrate that STAT3 attenuates the ability of STAT5 to promote the development of IL-9-secreting T cells. We demonstrate that production of IL-9 is increased in the absence of STAT3 and cytokines that result in a sustained activation of STAT3, including IL-6, have the greatest potency in repressing IL-9 production in a STAT3-dependent manner. Increased IL-9 production in the absence of STAT3 correlates with increased endogenous IL-2 production and STAT5 activation, and blocking IL-2 responses eliminates the difference in IL-9 production between wild-type and STAT3-deficient T cells. Moreover, transduction of developing Th9 cells with a constitutively active STAT5 eliminates the ability of IL-6 to reduce IL-9 production. Thus, STAT3 functions as a negative regulator of IL-9 production through attenuation of STAT5 activation and function. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
29. Treatment of Uveitis by In Situ Administration of Ex Vivo-Activated Polyclonal Regulatory T Cells.
- Author
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Grégoire, Sylvie, Terrada, Celine, Martin, Gaelle H., Fourcade, Gwladys, Baeyens, Audrey, Marodon, Gilles, Fisson, Sylvain, Billiard, Fabienne, Lucas, Bruno, Tadayoni, Ramin, Behar-Cohen, Francine, Levacher, Béatrice, Galy, Anne, LeHoang, Phuc, Klatzmann, David, Bodaghi, Bahram, and Salomon, Benoit L.
- Subjects
- *
SUPPRESSOR cells , *T cells , *UVEITIS , *INTERLEUKIN-10 , *REACTIVE oxygen species , *LABORATORY mice - Abstract
CD4+CD25+Foxp3+ regulatory T (Treg) cell therapy is a promising approach for the treatment of autoimmune diseases. To be effective, Treg cells should be in an activated state in the target tissue. This can be achieved by systemic administration of Ag-specific Treg cells, which are difficult to produce in conditions that can be translated to the clinic. In this paper, we propose an alternative approach consisting of in situ injection of preactivated polyclonal Treg cells that would exert bystander suppression in the target tissue. We show that polyclonal Treg cells suppressed uveitis in mice as efficiently as Ag-specific Treg cells but only when preactivated and administered in the vitreous. Uveitis control was correlated with an increase of IL-10 and a decrease of reactive oxygen species produced by immune cell infiltrates in the eye. Thus, our results reveal a new mechanism of Treg cell-mediated suppression and a new Treg cell therapy approach. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
30. The NLRP1 Inflammasome Attenuates Colitis and Colitis-Associated Tumorigenesis.
- Author
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Williams, Tere M., Leeth, Rachel A., Rothschild, Daniel E., Coutermarsh-Ott, Sheryl L., McDaniel, Dylan K., Simmons, Alysha E., Heid, Bettina, Cecere, Thomas E., and Allen, Irving C.
- Subjects
- *
DARDARIN , *INFLAMMATORY mediators , *GASTROINTESTINAL diseases , *NEOPLASTIC cell transformation , *INFLAMMATORY bowel diseases , *GENE expression , *PATHOGENIC microorganisms - Abstract
Nucleotide-binding domain and leucine-rich repeat (NLR) proteins are a diverse family of pattern recognition receptors that are essential mediators of inflammation and host defense in the gastrointestinal system. Recent studies have identified a subgroup of inflammasome forming NLRs that modulate the mucosal immune response during inflammatory bowel disease (IBD) and colitis associated tumorigenesis. To better elucidate the contribution of NLR family members in IBD and cancer, we conducted a retrospective analysis of gene expression metadata from human patients. These data revealed that NLRP1, an inflammasome forming NLR, was significantly dysregulated in IBD and colon cancer. To better characterize the function of NLRP1 in disease pathogenesis, we used Nlrp1b-/- mice in colitis and colitis-associated cancer models. In this paper, we report that NLRP1 attenuates gastrointestinal inflammation and tumorigenesis. Nlrp1b-/- mice demonstrated significant increases in morbidity, inflammation, and tumorigenesis compared with wild-type animals. Similar to data previously reported for related inflammsome forming NLRs, the increased inflammation and tumor burden was correlated with attenuated levels of IL-1ß and IL-18. Further mechanistic studies using bone marrow reconstitution experiments revealed that the increased disease pathogenesis in the Nlrp1b-/- mice was associated with nonhematopoietic-derived cells and suggests that NLRP1 functions in the colon epithelial cell compartment to attenuate tumorigenesis. Taken together, these data identify NLRP1 as an essential mediator of the host immune response during IBD and cancer. These findings are consistent with a model whereby multiple NLR inflammasomes attenuate disease pathobiology through modulating IL-1ß and IL-18 levels in the colon. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
31. E3 Ubiquitin Ligase Cbl-b Regulates Thymic-Derived CD4+CD25+ Regulatory T Cell Development by Targeting Foxp3 for Ubiquitination.
- Author
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Yixia Zhao, Hui Guo, Guilin Qiao, Mark Zucker, Langdon, Wallace Y., and Jian Zhang
- Subjects
- *
T cells , *UBIQUITIN ligases , *CD4 antigen , *CD25 antigen , *FORKHEAD transcription factors , *UBIQUITINATION , *CBL gene - Abstract
CD28 costimulation is essential for the development of thymic-derived CD4+CD25+Foxp3+ regulatory T cells ("tTregs"). E3 ubiquitin ligase Cbl-b has been shown to regulate CD28 dependence of T cell activation. In this paper, we report that the loss of Cbl-b partially but significantly rescues the defective development of tTregs in Cd28-/- mice. This partial rescue is independent of IL-2. Mechanistically, Cbl-b binds to Foxp3 upon TCR stimulation and, together with Stubl, targets Foxp3 for ubiquitination and subsequently degradation in the proteasome. As Cbl-b self-ubiquitination and proteasomal degradation is impaired in Cd28-/- T cells, the defective development of tTregs in Cd28-/- mice may in part be due to increased Foxp3 ubiquitination and degradation targeted by Stubl and Cbl-b. Treating Cd28-/- mice with a proteasome inhibitor completely rescues defective tTreg development in these mice. Therefore, Cbl-b, together with Stubl, ubiquitinate Foxp3, and regulate tTreg development. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
32. Elevation of c-MYC Disrupts HLA Class II-Mediated Immune Recognition of Human B Cell Tumors.
- Author
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God, Jason M., Cameron, Christine, Figueroa, Janette, Amria, Shereen, Hossain, Azim, Kempkes, Bettina, Bornkamm, Georg W., Stuart, Robert K., Blum, Janice S., and Haque, Azizul
- Subjects
- *
MYC proteins , *HLA class II antigens , *IMMUNOREGULATION , *BURKITT'S lymphoma , *ENOLASE , *B cell tumors - Abstract
Elevated levels of the transcription factor c-myc are strongly associated with various cancers, and in particular B cell lymphomas. Although many of c-MYC's functions have been elucidated, its effect on the presentation of Ag through the HLA class II pathway has not been reported previously. This is an issue of considerable importance, given the low immunogenicity of many c-MYCpositive tumors. We report in this paper that increased c-MYC expression has a negative effect on the ability of B cell lymphomas to functionally present Ags/peptides to CD4+ T cells. This defect was associated with alterations in the expression of distinct cofactors as well as interactions of antigenic peptides with class II molecules required for the presentation of class II-peptide complexes and T cell engagement. Using early passage Burkitt's lymphoma (BL| tumors and transformed cells, we show that compared with B lymphoblasts, BL cells express decreased levels of the class II editor HLA-DM, lysosomal thiol-reductase GILT, and a 47-kDa enolase-like protein. Functional Ag presentation was partially restored in BL cells treated with a c-MYC inhibitor, demonstrating the impact of this oncogene on Ag recognition. This restoration of HLA class II-mediated Ag presentation in early passage BL tumors/cells was linked to enhanced HLA-DM expression and a concurrent decrease in HLA-DO in BL cells. Taken together, these results reveal c-MYC exerts suppressive effects at several critical checkpoints in Ag presentation, which contribute to the immunoevasive properties of BL tumors. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
33. A Novel Antibody against Human Factor B that Blocks Formation of the C3bB Proconvertase and Inhibits Complement Activation in Disease Models.
- Author
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Subías, Marta, Tortajada, Agustín, Gastoldi, Sara, Galbusera, Miriam, López-Perrote, Andrés, de Juana Lopez, Lucia, González-Fernández, Fernando Ataúlfo, Villegas-Martínez, Ana, Dominguez, Mercedes, Llorca, Oscar, Noris, Marina, Morgan, B. Paul, and de Córdoba, Santiago Rodríguez
- Subjects
- *
ERYTHROCYTES , *MYASTHENIA gravis , *NEUROMUSCULAR diseases , *HEMOLYSIS & hemolysins , *HEMOGLOBINURIA , *HEMOLYTIC-uremic syndrome , *CARCINOGENESIS - Abstract
The alternative pathway (AP) is critical for the efficient activation of complement regardless of the trigger. It is also a major player in pathogenesis, as illustrated by the long list of diseases in which AP activation contributes to pathology. Its relevance to human disease is further emphasized by the high prevalence of pathogenic inherited defects and acquired autoantibodies disrupting components and regulators of the AP C3-convertase. Because pharmacological downmodulation of the AP emerges as a broad-spectrum treatment alternative, there is a powerful interest in developing new molecules to block formation and/or activity of the AP C3-convertase. In this paper, we describe the generation of a novel mAb targeting human factor B (FB). mAb FB48.4.2, recognizing with high affinity an evolutionary-conserved epitope in the Ba fragment of FB, very efficiently inhibited formation of the AP C3-proconvertase by blocking the interaction between FB and C3b. In vitro assays using rabbit and sheep erythrocytes demonstrated that FB28.4.2 was a potent AP inhibitor that blocked complement-mediated hemolysis in several species. Using ex vivo models of disease we demonstrated that FB28.4.2 protected paroxysmal nocturnal hemoglobinuria erythrocytes from complement-mediated hemolysis and inhibited both C3 fragment and C5b-9 deposition on ADP-activated HMEC-1 cells, an experimental model for atypical hemolytic uremic syndrome. Moreover, i.v. injection of FB28.4.2 in rats blocked complement activation in rat serum and prevented the passive induction of experimental autoimmune Myasthenia gravis. As a whole, these data demonstrate the potential value of FB28.4.2 for the treatment of disorders associated with AP complement dysregulation in man and animal models. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
34. Splenic Red Pulp Macrophages Cross-Prime Early Effector CTL That Provide Rapid Defense against Viral Infections.
- Author
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Enders, Marika, Franken, Lars, Philipp, Marie-Sophie, Kessler, Nina, Baumgart, Ann-Kathrin, Eichler, Melanie, Wiertz, Emmanuel J. H., Garbi, Natalio, and Kurts, Christian
- Subjects
- *
VIRUS diseases , *MACROPHAGES , *TRANSCRIPTION factors , *PULPING , *DENDRITIC cells - Abstract
Cross-presentation allows dendritic cells (DCs) to present peptides derived from endocytosed Ags on MHC class I molecules, which is important for activating CTL against viral infections and tumors. Type 1 classical DCs (cDC1), which depend on the transcription factor Batf3, are considered the main cross-presenting cells. In this study, we report that soluble Ags are efficiently cross-presented also by transcription factor SpiC-dependent red pulp macrophages (RPM) of the spleen. In contrast to cDC1, RPM used the mannose receptor for Ag uptake and employed the proteasome- and TAP-dependent cytosolic cross-presentation pathway, previously shown to be used in vitro by bone marrow-derived DCs. In an in vivo vaccination model, both cDC1 and RPM cross-primed CTL efficiently but with distinct kinetics. Within a few days, RPM induced very early effector CTL of a distinct phenotype (Ly6A/E+ Ly6C(+) KLRG1- CD127- CX3CR1- Grz-B+). In an adenoviral infection model, such CTL contained the early viral spread, whereas cDC1 induced short-lived effector CTL that eventually cleared the virus. RPM-induced early effector CTL also contributed to the endogenous antiviral response but not to CTL memory generation. In conclusion, RPM can contribute to antiviral immunity by generating a rapid CTL defense force that contains the virus until cDC1-induced CTL are available to eliminate it. This function can be harnessed for improving vaccination strategies aimed at inducing CTL. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
35. CXCL1 but Not IL-6 Is Required for Recurrent Herpetic Stromal Keratitis.
- Author
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West, Devin M., Del Rosso, Chelsea R., Xiao-Tang Yin, and Stuart, Patrick M.
- Subjects
- *
KERATITIS , *CORNEA diseases , *INFLAMMATION , *NEUTROPHILS , *CYTOKINES , *CHEMOKINES , *IMMUNOLOGY - Abstract
Herpetic stromal keratitis (HSK) is characterized by an inflammatory response that includes neutrophils, macrophages, NK cells, and T cells. The factors that are responsible for this inflammation are proinflammatory cytokines and chemokines. Many of these factors have been defined for primary disease, but relatively few have been investigated during recurrent HSK. The present study was designed to determine the role that two of these factors, IL-6 and CXCL1, play during recurrent HSK. Results clearly indicate that unlike primary disease, IL-6 plays no role in recurrent HSK. However, the presence of CXCL1 is required for recurrent HSK as evidenced by the lack of corneal disease in mice treated with anti-CXCL1 Ab. This was confirmed using mice lacking the primary receptor for CXCL1, CXCR2. Corneal disease in this strain was significantly reduced compared with wild-type C57BL/6 controls. Unexpectedly, lack of disease occurs even though CXCL1 knockout mice display increased viral shedding at the cornea. The primary mechanism that CXCL1 plays during disease is its ability to stimulate neutrophils to infiltrate the cornea following reactivation. This paper provides further evidence that primary HSK and recurrent HSK possess overlapping yet distinct disease mechanisms. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
36. Nanoparticle Adjuvant Sensing by TLR7 Enhances CD8+ T Cell-Mediated Protection from Listeria Monocytogenes Infection.
- Author
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Lebel, Marie-Ève, Daudelin, Jean-François, Chartrand, Karine, Tarrab, Esther, Kalinke, Ulrich, Savard, Pierre, Labrecque, Nathalie, Leclerc, Denis, and Lamarre, Alain
- Subjects
- *
IMMUNOLOGICAL adjuvants , *MOSAIC viruses , *TOLL-like receptors , *T cell receptors , *LISTERIA monocytogenes , *PREVENTION - Abstract
Developing new adjuvants and vaccination strategies is of paramount importance to successfully fight against many life-threatening infectious diseases and cancer. Very few adjuvants are currently authorized for human use, and these mainly stimulate a humoral response. However, specific Abs are not sufficient to confer protection against persisting infections or cancer. Therefore, development of adjuvants and immunomodulators able to enhance cell-mediated immune responses represents a major medical need. We recently showed that papaya mosaic virus nanoparticles (PapMV), self-assembled from the coat protein of a plant virus and a noncoding ssRNA molecule, are highly immunogenic in mice. PapMV can be used either as a vaccine delivery platform, through fusion of various epitopes to the coat protein or as adjuvant to enhance humoral immune responses against coadministered Ags or vaccines. However, the mechanisms that confer these immunomodulatory properties to PapMV and its ability to enhance T cell vaccines remain unknown. Using immunization studies in mice, we demonstrate in this paper that PapMV represents a novel TLR7 agonist with strong immunostimulatory properties. More importantly, pretreatment with PapMV significantly improves effector and memory CD8+ T cell responses generated through dendritic cell vaccination increasing protection against a Listeria monocytogenes challenge. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
37. The Response of Secondary Genes to Lipopolysaccharides in Macrophages Depends on Histone Deacetylase and Phosphorylation of C/EBPα.
- Author
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Serrat, Neus, Sebastian, Carlos, Pereira-Lopes, Selma, Valverde-Estrella, Lorena, Lloberas, Jorge, and Celada, Antonio
- Subjects
- *
LIPOPOLYSACCHARIDES , *MACROPHAGES , *HISTONE deacetylase , *PHOSPHORYLATION , *TRICHOSTATIN A - Abstract
LPS induces the expression of NO synthase 2 (nos2) in macrophages. The expression of this molecule is one of the hallmarks of classical activation. In this paper, we describe that trichostatin A (TSA), which inhibits deacetylase activity, blocks LPS-dependent nos2 expression. TSA specifically inhibits LPS-dependent genes of secondary response, which require new protein synthesis for their induction but not those belonging to the primary response, which do not depend on this process. Deacetylase activity acts at the transcriptional level because RNA polymerase II was not bound after LPS stimulus when we added TSA. A link between the global acetylation caused by HDAC inhibitor and gene promoter recruitment of CDK8 was found. This Mediator complex subunit associates with Med 12, Med13, and cyclin C to form a submodule that is a transcriptional negative regulator. We also found that TSA reduces C/EBPβ phosphorylation without affecting its binding to DNA. Taken together, these results shed light on the molecular mechanisms involved in the transcriptional regulation of LPS-treated macrophages and on how TSA targets critical LPS-induced genes, such as nos2 and tnf-α, in inflammatory macrophage response. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
38. Unique Features of Naive CD8+ T Cell Activation by IL-2.
- Author
-
Jae-Ho Cho, Hee-Ok Kim, Kyu-Sik Kim, Deok-Hwan Yang, Surh, Charles D., and Sprent, Jonathan
- Subjects
- *
INTERLEUKIN-2 , *T cells , *IMMUNE system , *TYROSINE , *IMMUNOSPECIFICITY - Abstract
IL-2 has a pervasive influence on the immune system and dictates the survival and differentiation of multiple T cell subsets, including CD4 regulatory T cells, CD4 Th cells, and CD8 memory cells. IL-2 is synthesized by T cells during the early stages of the immune response and promotes T cell expansion and effector cell generation after initial activation via TCR signaling. Based on studies with activated T cell lines maintained in vitro, IL-2 is known to activate multiple signaling pathways that show considerable overlap with the pathways elicited via the TCR. In this paper, we have examined IL-2 signaling under TCR-independent conditions, namely by culturing purified resting naive CD8 T cells with IL-2 in the absence of Ag or APC. Under these conditions, we show in this study that IL-2 elicits a unique pattern of signaling associated with strong lymphocyte-specific protein tyrosine kinase/JAK3-dependent activation of the PI3K/AKT pathway with little or no involvement of STAT5, NF-κB, or the calcineurin/NFAT pathways. Such signaling induces marked proliferation associated with rapid and selective expression of eomesodermin but not T-bet and differentiation into long-lived central memory cells after adoptive transfer. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
39. Exploiting Apoptosis for Therapeutic Tolerance Induction.
- Author
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Getts, Daniel R., McCarthy, Derrick P., and Miller, Stephen D.
- Subjects
- *
APOPTOSIS , *IMMUNOLOGIC diseases , *ETHYLENE , *AUTOIMMUNITY , *IMMUNOGLOBULIN E - Abstract
Immune tolerance remains the most promising yet elusive strategy for treating immune-mediated diseases. An experimental strategy showing promise in phase 1 clinical studies is the delivery of Ag cross-linked to apoptotic leukocytes using ethylene carbodiimide. This approach originated from demonstration of the profound tolerance-inducing ability of i.v. administered Ag-coupled splenocytes (Ag-SP) in mice, which has been demonstrated to treat T cell- mediated disorders including autoimmunity, allergy, and transplant rejection. Recent studies have defined the intricate interplay between the innate and adaptive immune systems in Ag-SP tolerance induction. Innate mechanisms include scavenger receptor-mediated uptake of Ag-SP by host APCs, Ag representation, and the required upregulation of PD-L1 expression and IL-10 production by splenic marginal zone macrophages leading to Ag-specific T cell regulation via the combined effects of cell-intrinsic anergy and regulatory T cell induction. In this paper, we discuss the history, advantages, current mechanistic understanding, and clinical potential of tolerance induction using apoptotic Ag-coupled apoptotic leukocytes. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
40. Differential Impact of Age and Cytomegalovirus Infection on the γδ T Cell Compartment.
- Author
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Roux, Antoine, Mourin, Gisèle, Larsen, Martin, Fastenackels, Solène, Urrutia, Alejandra, Gorochov, Guy, Autran, Brigitte, Donner, Catherine, Sidi, Daniel, Sibony-Prat, Joyce, Marchant, Arnaud, Stern, Marc, Sauce, Delphine, and Appay, Victor
- Subjects
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T cells , *CYTOMEGALOVIRUS diseases , *AGING -- Immunological aspects , *CELL compartmentation , *T cell differentiation , *CELLULAR aging , *IMMUNOLOGY , *PHYSIOLOGY - Abstract
γδ T cells represent a subset of unconventional T lymphocytes that are known for their reactivity against different pathogens and considered as intermediate mediators between adaptive and innate immunity. We provide in this paper further insights underlying the changes that affect the γδ T cell compartment with advanced age in humans. We show that both aging and CMV infection impact independently on the γδ T cell compartment. Most γδ T cells are significantly affected by age and present a decreased frequency in the elderly. The decline of the γδ T cell pool appears to be independent from the activity of the thymus, arguing in favor of an extrathymic site of γδ T cell production in humans. Of note, CMV infection, which is directly associated with the activation of the pool of Vδ2− γδ T cells, promotes nonetheless the inflation of this compartment throughout life. CMV seropositivity accentuates further the accumulation of highly differentiated lymphocytes in Vδ2− γδ T cell subsets with time, in contrast to Vδ2+ γδ T cells, which maintain a less differentiated phenotype. This is similar to the effect of CMV on αβ T cells and suggests that γδ T cells may vary in differentiation phenotype according to distinct stimuli or pathogens. [ABSTRACT FROM AUTHOR]
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- 2013
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41. Human Plasmacytoid Dendritic Cells Efficiently Capture HIV-1 Envelope Glycoproteins via CD4 for Antigen Presentation.
- Author
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Sandgren, Kerrie J., Smed-Sörensen, Anna, Forsell, Mattias N., Soldemo, Martina, Adams, William C., Liang, Frank, Perbeck, Leif, Koup, Richard A., Wyatt, Richard T., Karlsson Hedestam, Gunilla B., and Loré, Karin
- Subjects
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DENDRITIC cells , *GLYCOPROTEINS , *CD4 antigen , *AIDS vaccines , *HUMORAL immunity , *PHYSIOLOGY - Abstract
Advances in HIV-1 vaccine clinical trials and preclinical research indicate that the virus envelope glycoproteins (Env) are likely to be an essential component of a prophylactic vaccine. Efficient Ag uptake and presentation by dendritic cells (DCs) is important for strong CD4+ Th cell responses and the development of effective humoral immune responses. In this study, we examined the capacity of distinct primary human DC subsets to internalize and present recombinant Env to CD4+ T cells. Consistent with their specific receptor expression, skin DCs bound and internalized Env via C-type lectin receptors, whereas blood DC subsets, including CD1c+ myeloid DCs, CD123+ plasmacytoid DCs (PDCs), and CD141+ DCs exhibited a restricted repertoire of C-type lectin receptors and relied on CD4 for uptake of Env. Despite a generally poor capacity for Ag uptake compared with myeloid DCs, the high expression of CD4 on PDCs allowed them to bind and internalize Env very efficiently. CD4-mediated uptake delivered Env to EEA1+ endosomes that progressed to Lamp1+ and MHC class II+ lysosomes where internalized Env was degraded rapidly. Finally, all three blood DC subsets were able to internalize an Env-CMV pp65 fusion protein via CD4 and stimulate pp65-specific CD4+ T cells. Thus, in the in vitro systems described in this paper, CD4-mediated uptake of Env is a functional pathway leading to Ag presentation, and this may therefore be a mechanism used by blood DCs, including PDCs, for generating immune responses to Env-based vaccines. [ABSTRACT FROM AUTHOR]
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- 2013
- Full Text
- View/download PDF
42. TRPC6 Regulates CXCR2-Mediated Chemotaxis of Murine Neutrophils.
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Lindemann, Otto, Umlauf, Daniel, Frank, Svetlana, Schimmelpfennig, Sandra, Bertrand, Jessica, Pap, Thomas, Hanley, Peter J., Fabian, Anke, Dietrich, Alexander, and Schwab, Albrecht
- Subjects
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TRP channels , *CHEMOTAXIS , *NEUTROPHILS , *MITOGEN-activated protein kinases , *PROTEIN kinase B , *CHEMOKINES , *IMMUNOREGULATION , *LABORATORY mice - Abstract
Unraveling the mechanisms involved in chemotactic navigation of immune cells is of particular interest for the development of new immunoregulatory therapies. It is generally agreed upon that members of the classical transient receptor potential channel family (TRPC) are involved in chemotaxis. However, the regulatory role of TRPC channels in chemoattractant receptor-mediated signaling has not yet been clarified in detail. In this study, we demonstrate that the TRPC6 channels play a pronounced role in CXCR2-mediated intermediary chemotaxis, whereas N-formyl-methionine-leucine-phenylalanine receptor-mediated end-target chemotaxis is TRPC6 independent. The knockout of TRPC6 channels in murine neutrophils led to a strongly impaired intermediary chemotaxis after CXCR2 activation which is not further reinforced by CXCR2, PI3K, or p38 MAPK inhibition. Furthermore, CXCR2-mediated Ca2+ influx but not Ca2+ store release was attenuated in TRPC6-/- neutrophils. We demonstrate that the TRPC6 deficiency affected phosphorylation of AKT and MAPK downstream of CXCR2 receptor activation and led to altered remodeling of actin. The relevance of this TRPC6-depending defect in neutrophil chemotaxis is underscored by our in vivo findings. A nonseptic peritoneal inflammation revealed an attenuated recruitment of neutrophils in the peritoneal cavity of TRPC6-/- mice. In summary, this paper defines a specific role of TRPC6 channels in CXCR2-induced intermediary chemotaxis. In particular, TRPC6-mediated supply of calcium appears to be critical for activation of downstream signaling components. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
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43. GATA-3 Regulates the Homeostasis and Activation of CD8+ T Cells.
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Tzong-Shyuan Tai, Sung-Yun Pai, and I-Cheng Ho
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GENETIC regulation , *HOMEOSTASIS , *ENZYME activation , *CD8 antigen , *T cells , *TRANSCRIPTION factors , *CYTOKINES - Abstract
GATA-3, a C2C2-type zinc finger transcription factor, regulates many steps of T cell development and differentiation. It is also required for optimal production of type 2 cytokines by CD8+ T cells. However, its role in the development and function of this subset of T cells is still poorly characterized. In this paper, we report that GATA-3 is required for MHC-mediated positive selection and final maturation of CD8 single-positive thymocytes. Deficiency of GATA-3 mediated by a CD4cre transgene led to age-dependent lymphadenopathy partly because of abnormal expansion of CD8+ T cells driven by a cell-extrinsic mechanism. Paradoxically, GATA-3-deficient CD8+ T cells were hyporesponsive to Ag stimulation due to a defect in the maintenance/ progression, but not initiation, of activation signals. More importantly, GATA-3-deficient CD8+ T cells were less efficient in killing Ag-bearing tumor cells in vivo. Taken together, our data further expand the role of GATA-3 in T cells. [ABSTRACT FROM AUTHOR]
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- 2013
- Full Text
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44. Isolation of Human CD4/CD8 Double-Positive, Graft-Versus-Host Disease-Protective, Minor Histocompatibility Antigen-Specific Regulatory T Cells and of a Novel HLA-DR7-Restricted HY-Specific CD4 Clone.
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Eljaafari, Assia, Yuruker, Ozel, Ferrand, Christophe, Farre, Annie, Addey, Caroline, Tartelin, Marie-Laure, Thomas, Xavier, Tiberghien, Pierre, Simpson, Elizabeth, Rigal, Dominique, and Scott, Diane
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GRAFT versus host disease , *HLA histocompatibility antigens , *T cells , *MOLECULAR cloning , *GENE expression , *CELL membranes - Abstract
Minor histocompatibility (H) Ags are classically described as self-peptides derived from intracellular proteins that are expressed at the cell surface by MHC class I and class II molecules and that induce T ceil alloresponses. We have isolated three different T cell populations from a skin biopsy of a patient suffering from acute graft-versus-host disease following sex-mismatched HLA-identical bone marrow transplantation. The first population was: 1) CD4+/CD8+ double-positive; 2) specific for an HLA class I-restricted autosomal Ag; 3) expressed a Trl profile with high levels of IL-10, but low IL-2 and IFN-γ; and 4) exerted regulatory function in the presence of recipient APCs. The second was CD8 positive, specific for an HLA class I-restricted autosomally encoded minor H Ag, but was only weakly cytotoxic. The third was CD4 single positive, specific for an HLA-DR7-restricted HY epitope and exerted both proliferative and cytotoxic functions. Identification of the peptide recognized by these latter cells revealed a new human HY epitope, TGKIINFIKFDTGNL, encoded by RPS4Y and restricted by HLA-DR7. In this paper, we show human CD4/CD8 double-positive, acute graft-versus-host disease-protective, minor H Ag-specific regulatory T cells and identify a novel HLA-DR7/ HY T cell epitope, encoded by RPS4Y, a potential new therapeutic target. [ABSTRACT FROM AUTHOR]
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- 2013
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45. Local Complement-Targeted Intervention in Periodontitis: Proof-of-Concept Using a C5a Receptor (CD88) Antagonist.
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Abe, Toshiharu, Hosur, Kavita B., Hajishengallis, Evlambia, Reis, Edimara S., Ricklin, Daniel, Lambris, John D., and Hajishengallis, George
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PERIODONTITIS , *CHEMOKINE receptors , *INFLAMMATION , *TOLL-like receptors , *TISSUES , *INTERLEUKINS , *LABORATORY mice - Abstract
When excessively activated or deregulated, complement becomes a major link between infection and inflammatory pathology in-cluding periodontitis. This oral inflammatory disease is associated with a dysbiotic microbiota, leads to the destruction of bone and other tooth-supporting structures, and exerts an adverse impact on systemic health. We have previously shown that mice deficient either in complement C5a receptor (C5aR; CD88) or TLR2 are highly and similarly resistant to periodontitis, suggesting that a cross-talk between the two receptors may be involved in the disease process. In this paper, we show that C5aR and TLR2 indeed synergize for maximal inflammatory responses in the periodontal tissue and uncover a novel pharmacological target to abrogate periodontitis. Using two different mouse models of periodontitis, we show that local treatments with a C5aR antagonist inhibited periodontal inflammation through downregulation of TNF, IL-lβ, IL-6, and IL-17 and further protected against bone loss, regardless of the presence of TLR2. These findings not only reveal a crucial cooperation between C5aR and TLR2 in periodontal inflammation but also provide proof-of-concept for local targeting of C5aR as a powerful candidate for the treatment of human periodontitis. [ABSTRACT FROM AUTHOR]
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- 2012
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46. Abelson Tyrosine Kinase Controls Phagosomal Acidification Required for Killing of Mycobacterium tuberculosis in Human Macrophages.
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Bruns, Heiko, Stegelmann, Frank, Fabri, Mario, Dӧhner, Konstanze, van Zandbergen, Ger, Wagner, Manfred, Skinner, Mhairi, Modlin, Robert L., and Stenger, Steffen
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PROTEIN-tyrosine kinases , *MYCOBACTERIUM tuberculosis , *MACROPHAGES , *TUBERCULOSIS prevention , *ORGANELLES , *BACTERIAL cells , *GENE silencing , *GENE expression in bacteria , *ANTI-infective agents , *DRUG activation - Abstract
The mechanisms that regulate the acidification of intracellular compartments are key to host defense against pathogens. In this paper, we demonstrate that Abl tyrosine kinase, a master switch for cell growth and trafficking of intracellular organelles, controls the acidification of lysosomes in human macrophages. Pharmacological inhibition by imatinib and gene silencing of Abelson (Abl) tyrosine kinase reduced the lysosomal pH in human macrophages by increasing the transcription and expression of the proton pumping enzyme vacuolar-type H+-adenosine triphosphatase. Because lysosomal acidification is required for antimicrobial ac-tivity against intracellular bacteria, we determined the effect of imatinib on the growth of the major human pathogen Mycobac-terium tuberculosis. Imatinib limited the multiplication of M. tuberculosis, and growth restriction was dependent on acidification of the mycobacterial compartment. The effects of imatinib were also active in vivo because circulating monocytes from imatinib-treated leukemia patients were more acidic than monocytes from control donors. Importantly, sera from imatinib-treated patients triggered acidification and growth restriction of M. tuberculosis in macrophages. In summary, our results identify the control of phagosomal acidification as a novel function of Abl tyrosine kinase and provide evidence that the regulation occurs on the level of the vacuolar-type H+-adenosine triphosphatase. Given the efficacy of imatinib in a mouse model of tuberculosis and our finding that orally administered imatinib increased the ability of human serum to trigger growth reduction of intracellular M. tubercu-losis, clinical evaluation of imatinib as a complementary therapy of tuberculosis, in particular multidrug or extremely drug-resistant disease, is warranted. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
47. Caveolin-1-Mediated Negative Signaling Plays a Critical Role in the Induction of Regulatory Dendritic Cells by DNA and Protein Coimmunization.
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Jinyao Li, Shuang Geng, Xiaoping Xie, Hu Liu, Guoxing Zheng, Xiaolin Sun, Gan Zhao, Ying Wan, Yuzhang Wu, Xuan Chen, Yiwei Zhong, and Bin Wang
- Subjects
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CAVEOLINS , *CELLULAR signal transduction , *DENDRITIC cells , *CELLULAR control mechanisms , *AUTOIMMUNE disease treatment , *T cells , *DNA , *INTERLEUKIN-10 - Abstract
Induction of Ag-speciflc regulatory T cells (iTregs) by vaccination is a promising strategy for treating autoimmune diseases. We previously demonstrated that DNA and protein covaccination converted naive T cells to Ag-speciflc iTregs by inducing CD11c+ CD40lowIL-10+ regulatory dendritic cells (DCregs). However, it is unclear how coimmunization induces the DCregs. In this paper, we report that the event is initiated by coentry of sequence-matched DNA and protein immunogens into the same DC via caveolae-mediated endocytosis, which leads to inhibition of phosphorylation of caveolin-1 (Cav-1), the main component of caveolae, and upregulation of Tollip. This triggers downstream signaling that upregulates suppressor of cytokine signaling 1 and downregulates NF-kB and STAT-l&agr;. Silencing either Cav-1 or Tollip blocks the negative signaling, leading to upregulated expression of CD40, downregulated production of IL-10, and loss of iTreg-inducing function. We further show that DCregs can be induced in culture from primary DCs and JAWS II DC lines by feeding them sequence-matched DNA and protein immunogens. The in vitro-generated DCregs are effective in ameliorating autoimmune and inflammatory diseases in several mouse models. Our study thus suggests that DNA and protein coimmunization induces DCregs through Cav-1- and Tollip-mediated negative signaling. It also describes a novel method for generating therapeutic DCregs in vitro. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
48. Inhibition of JAKs in Macrophages Increases Lipopolysaccharide-Induced Cytokine Production by Blocking IL-10-Mediated Feedback.
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Pattison, Michael J., MacKenzie, Kirsty F., and Arthur, J. Simon C.
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MACROPHAGES , *LIPOPOLYSACCHARIDES , *CYTOKINES , *INTERLEUKIN-10 , *TOLL-like receptors , *PHYSIOLOGICAL control systems , *TUMOR necrosis factors , *STAT proteins , *CELLULAR signal transduction - Abstract
Macrophages are an important source of cytokines following infection. Stimulation of macrophages with TLR agonists results in the secretion of TNF-&agr;, IL-6, and IL-12, and the production of these cytokines is controlled by multiple feedback pathways. Macrophages also produce IL-10, which acts to inhibit proinflammatory cytokine production by macrophages via a JAK/STAT3-dependent pathway. We show in this paper that, Ruxolitinib, a recently described selective inhibitor of JAKs, increases TNF, IL-6, and IL-12 secretion in mouse bone marrow-derived macrophages stimulated with LPS. This effect is largely due to its ability to block IL-10-mediated feedback inhibition on cytokine transcription in macrophages. Similar results were also obtained with a second structurally unrelated Jak inhibitor, Tofacitinib. In addition, LPS induced the production of IFN-&bgr;, which was then able to activate JAKs in macrophages, resulting in the stimulation of STATl phosphorylation. The initial induction of IL-10 was independent of JAK signaling; however, inhibition of JAKs did reduce IL-10 secretion at later time points. This reflected a requirement for the IFN-&bgr; feedback loop to sustain IL-10 transcription following LPS stimulation. In addition to IL-10, IFN-ß also helped sustain IL-6 and IL-12 transcription. Overall, these results suggest that inhibition of JAKs may increase the inflammatory potential of macrophages stimulated with TLR4 agonists. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
49. Immune Surveillance Properties of Human NK Cell-Derived Exosomes.
- Author
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Lugini, Luana, Cecchetti, Serena, Huber, Veronica, Luciani, Francesca, Macchia, Gianfranco, Spadaro, Francesca, Paris, Luisa, Abalsamo, Laura, Colone, Marisa, Molinari, Agnese, Podo, Franca, Rivoltini, Licia, Ramoni, Carlo, and Fais, Stefano
- Subjects
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KILLER cells , *EXOSOMES , *CANCER cells , *CELL culture , *HEMATOPOIETIC stem cells , *NATURAL immunity , *BIOMARKERS - Abstract
Exosomes are nanovesicles released by normal and tumor cells, which are detectable in cell culture supernatant and human biological fluids, such as plasma. Functions of exosomes released by "normal" cells are not well understood. In fact, several studies have been carried out on exosomes derived from hematopoietic cells, but very little is known about NK cell exosomes, despite the importance of these cells in innate and adaptive immunity. In this paper, we report that resting and activated NK cells, freshly isolated from blood of healthy donors, release exosomes expressing typical protein markers of NK cells and containing killer proteins (i.e., Fas ligand and perforin molecules). These nanovesicles display cytotoxic activity against several tumor cell lines and activated, but not resting, immune cells. We also show that NK-derived exosomes undergo uptake by tumor target cells but not by resting PBMC. Exosomes purified from plasma of healthy donors express NK cell markers, including CD56+ and perforin, and exert cytotoxic activity against different human tumor target cells and activated immune cells as well. The results of this study propose an important role of NK cell-derived exosomes in immune surveillance and homeostasis. Moreover, this study supports the use of exosomes as an almost perfect example of biomimetic nanovesicles possibly useful in future therapeutic approaches against various diseases, including tumors. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
50. Chitin Elicits CCL2 from Airway Epithelial Cells and Induces CCR2-Dependent Innate Allergic Inflammation in the Lung.
- Author
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Roy, René M., Wüthrich, Marcel, and Klein, Bruce S.
- Subjects
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EPITHELIAL cells , *MACROPHAGE activation , *REACTIVE oxygen species , *CHITIN , *CHEMOKINE receptors , *CELLULAR signal transduction , *EOSINOPHILIA , *PNEUMONIA - Abstract
Chitin exposure in the lung induces eosinophilia and alternative activation of macrophages and is correlated with allergic airway disease. However, the mechanism underlying chitin-induced polarization of macrophages is poorly understood. In this paper, we show that chitin induces alternative activation of macrophages in vivo but does not do so directly in vitro. We further show that airway epithelial cells bind chitin in vitro and produce CCL2 in response to chitin both in vitro and in vivo. Supernatants of chitin-exposed epithelial cells promoted alternative activation of macrophages in vitro, whereas Ab neutralization of CCL2 in the super-nate abolished the alternative activation of macrophages. CCL2 acted redundantly in vivo, but mice lacking the CCL2 receptor, CCR2, showed impaired alternative activation of macrophages in response to chitin, as measured by arginase I, CCL17, and CCL22 expression. Furthermore, CCR2 knockout mice exposed to chitin had diminished reactive oxygen species products in the lung, blunted eosinophil and monocyte recruitment, and impaired eosinophil functions as measured by expression of CCL5, IL-13, and CCL11. Thus, airway epithelial cells secrete CCL2 in response to chitin and CCR2 signaling mediates chitin-induced alternative activation of macrophages and allergic inflammation in vivo. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
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