المؤلفون: Katrin Moira Heim, Martin E. Kreis, Stefan Angermair, Fabian Halleck, Arne Sattler, Katja Kotsch, Helena Stockmann, Dmytro Khadzhynov, Sascha Treskatsch

المصدر: J Clin Invest

مصطلحات موضوعية: Adult, Male, 0301 basic medicine, Cellular immunity, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), T cell, Programmed Cell Death 1 Receptor, Severity of Illness Index, Interferon-gamma, 03 medical and health sciences, 0302 clinical medicine, Intensive care, medicine, Humans, Aged, Aged, 80 and over, SARS-CoV-2, business.industry, Age Factors, COVID-19, General Medicine, T helper cell, Middle Aged, Th1 Cells, medicine.disease, Comorbidity, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Immunology, Commentary, Interleukin-2, Female, Disease Susceptibility, business, Ex vivo

الوصف: Coronavirus disease 2019 (COVID-19) has emerged as a global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). So far, viral targets of cellular immunity and factors determining successful mounting of T cell responses are poorly defined. We therefore analyzed cellular responses to membrane, nucleocapsid, and spike proteins in individuals suffering from moderate or severe infection and in individuals who recovered from mild disease. We demonstrate that the CoV-2-specific CD4+ T helper cell response is directed against all 3 proteins with comparable magnitude, ex vivo proliferation, and portions of responding patients. However, individuals who died were more likely to have not mounted a cellular response to the proteins. Higher patient age and comorbidity index correlated with increased frequencies of CoV-2-specific CD4+ T cells, harboring higher portions of IL-2-secreting, but lower portions of IFN-γ-secreting, cells. Diminished frequencies of membrane protein-reactive IFN-γ+ T cells were particularly associated with higher acute physiology and chronic health evaluation II scores in patients admitted to intensive care. CoV-2-specific T cells exhibited elevated PD-1 expression in patients with active disease as compared with those individuals who recovered from previous mild disease. In summary, our data suggest a link between individual patient predisposition with respect to age and comorbidity and impairment of CoV-2-specific Th1-type cellular immunity, thereby supporting a concept of altered T cell function in at-risk patients.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9e03688bab38d81eca8efbaf0e659dfaTest
https://doi.org/10.1172/jci140965Test

المؤلفون: Maria Fernandez Rubin De Celis, Diane Mathis, Archana Vijayakumar, Pedro M. Moraes-Vieira, Dionicio Siegel, Alan Saghatelian, Ismail Syed, James F. Mohan, Barbara B. Kahn, Andrew T. Nelson

المصدر: J Clin Invest

مصطلحات موضوعية: Adult, Male, 0301 basic medicine, endocrine system, medicine.medical_specialty, endocrine system diseases, Cell Survival, T-Lymphocytes, T cell, Palmitic Acid, Nod, Diabetes Mellitus, Experimental, Islets of Langerhans, Mice, 03 medical and health sciences, 0302 clinical medicine, Immune system, Mice, Inbred NOD, Insulin-Secreting Cells, Internal medicine, medicine, Animals, Humans, Insulin, B cell, Aged, NOD mice, Cell growth, Chemistry, Esters, General Medicine, Glucose Tolerance Test, Middle Aged, medicine.disease, Diabetes Mellitus, Type 1, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, Immune System, 030220 oncology & carcinogenesis, Commentary, Female, Insulitis, Stearic Acids, CD8

الوصف: Palmitic acid esters of hydroxy stearic acids (PAHSAs) are endogenous antidiabetic and antiinflammatory lipids. Here, we show that PAHSAs protect against type 1 diabetes (T1D) and promote β cell survival and function. Daily oral PAHSA administration to nonobese diabetic (NOD) mice delayed the onset of T1D and markedly reduced the incidence of T1D, whether PAHSAs were started before or after insulitis was established. PAHSAs reduced T and B cell infiltration and CD4+ and CD8+ T cell activation, while increasing Treg activation in pancreata of NOD mice. PAHSAs promoted β cell proliferation in both NOD mice and MIN6 cells and increased the number of β cells in NOD mice. PAHSAs attenuated cytokine-induced apoptotic and necrotic β cell death and increased β cell viability. The mechanism appears to involve a reduction of ER stress and MAPK signaling, since PAHSAs lowered ER stress in NOD mice, suppressed thapsigargin-induced PARP cleavage in human islets, and attenuated ERK1/2 and JNK1/2 activation in MIN6 cells. This appeared to be mediated in part by glucagon-like peptide 1 receptor (GLP-1R) and not the G protein-coupled receptor GPR40. PAHSAs also prevented impairment of glucose-stimulated insulin secretion and improved glucose tolerance in NOD mice. Thus, PAHSAs delayed the onset of T1D and reduced its incidence by attenuating immune responses and exerting direct protective effects on β cell survival and function.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::499e34da0668ce296976fc5094ee51f3Test
https://doi.org/10.1172/jci122445Test

المؤلفون: John R. Jimah, Manuel Duarte, Nick Huang, Tiffany Caza, Miguel Beckford, Katalin Banki, Eric M. Poeschla, Hind J. Fadel, Ryan Kelly, Aparna Godavarthy, David Fernandez, Joshua Lewis, Andras Perl

مصطلحات موضوعية: 0301 basic medicine, Adult, DNA (Cytosine-5-)-Methyltransferase 1, Adolescent, T cell, T-Lymphocytes, Receptors, Antigen, T-Cell, DNA methyltransferase, Epigenesis, Genetic, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Transcription (biology), medicine, Humans, Lupus Erythematosus, Systemic, Epigenetics, Enhancer, Mechanistic target of rapamycin, PI3K/AKT/mTOR pathway, Alleles, Adaptor Proteins, Signal Transducing, Aged, biology, Nuclear Respiratory Factor 1, TOR Serine-Threonine Kinases, Endogenous Retroviruses, Terminal Repeat Sequences, General Medicine, DNA Methylation, Middle Aged, HCT116 Cells, Molecular biology, Long terminal repeat, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, biology.protein, Female, Research Article, HeLa Cells, Transcription Factors

الوصف: Overexpression and long terminal repeat (LTR) polymorphism of the HRES‑1/Rab4 human endogenous retrovirus locus have been associated with T cell activation and disease manifestations in systemic lupus erythematosus (SLE). Although genomic DNA methylation is diminished overall in SLE, its role in HRES-1/Rab4 expression is unknown. Therefore, we determined how lupus-associated polymorphic rs451401 alleles of the LTR regulate transcription from the HRES-1/Rab4 promoter and thus affect T cell activation. The results showed that cytosine(–119) is hypermethylated while cytosine(–51) of the promoter and the LTR enhancer are hypomethylated in SLE. Pharmacologic or genetic inactivation of DNA methyltransferase 1 augmented the expression of HRES-1/Rab4. The minimal promoter was selectively recognized by metabolic stress sensor NRF1 when cytosine(–119) but not cytosine(–51) was methylated, and NRF1 stimulated HRES-1/Rab4 expression in human T cells. In turn, IRF2 and PSIP1 bound to the LTR enhancer and exerted control over HRES-1/Rab4 expression in rs451401 genotype– and methylation-dependent manners. The LTR enhancer conferred markedly greater expression of HRES-1/Rab4 in subjects with rs451401CC over rs451401GG alleles that in turn promoted mechanistic target of rapamycin (mTOR) activation upon T cell receptor stimulation. HRES-1/Rab4 alone robustly activated mTOR in human T cells. These findings identify HRES-1/Rab4 as a methylation- and rs451401 allele–dependent transducer of environmental stress and controller of T cell activation.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::bd0948814ebdf568c5f45b11a8c916dbTest
https://europepmc.org/articles/PMC7030820Test/

المؤلفون: Kevan C. Herold, Gilbert Y. Wong, Tenshang Joh, Shobha Potluri, Peter A. Gottlieb, Bruce W. Bode, Matteo Levisetti, Janet B. McGill, Megan Shannon, Bishu J Ganguly, Jing W. Hughes, Samantha L. Bucktrout, Desmond A. Schatz, Stephen E. Gitelman, Jeremy Pettus, Xiao Wang, Pamela D. Garzone, Chandrasekhar Udata

المصدر: JCI Insight. 4

مصطلحات موضوعية: Adult, CD4-Positive T-Lymphocytes, Male, 0301 basic medicine, Cell Survival, medicine.drug_class, medicine.medical_treatment, T cell, Dose-Response Relationship, Immunologic, CD8-Positive T-Lymphocytes, Antibodies, Monoclonal, Humanized, Monoclonal antibody, Interleukin-7 Receptor alpha Subunit, 03 medical and health sciences, 0302 clinical medicine, Immune system, medicine, Humans, Type 1 diabetes, Dose-Response Relationship, Drug, biology, business.industry, Interleukin-7, General Medicine, Middle Aged, medicine.disease, Diabetes Mellitus, Type 1, Treatment Outcome, 030104 developmental biology, Cytokine, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Immunology, Monoclonal, biology.protein, Female, Antibody, business, Immunologic Memory, CD8, Signal Transduction, Research Article

الوصف: BACKGROUND. The cytokine IL-7 is critical for T cell development and function. We performed a Phase Ib study in patients with type 1 diabetes (T1D) to evaluate how blockade of IL-7 would affect immune cells and relevant clinical responses. METHODS. Thirty-seven subjects with T1D received s.c. RN168, a monoclonal antibody that blocks the IL -7 receptor α (IL7Rα) in a dose-escalating study. RESULTS. Between 90% and 100% IL-7R occupancy and near-complete inhibition of pSTAT5 was observed at doses of RN168 1 mg/kg every other week (Q2wk) and greater. There was a significant decline in CD4(+) and CD8(+) effector and central memory T cells and CD4(+) naive cells, but there were fewer effects on CD8(+) naive T cells. The ratios of Tregs to CD4(+) or CD8(+) effector and central memory T cells versus baseline were increased. RNA sequencing analysis showed downmodulation of genes associated with activation, survival, and differentiation of T cells. Expression of the antiapoptotic protein Bcl-2 was reduced. The majority of treatment-emergent adverse events (TEAEs) were mild and not treatment related. Four subjects became anti–EBV IgG(+) after RN168, and 2 had symptoms of active infection. The immunologic response to tetanus toxoid was preserved at doses of 1 and 3 mg/kg Q2wk but reduced at higher doses. CONCLUSIONS. This trial shows that, at dosages of 1–3 mg/kg, RN168 selectively inhibits the survival and activity of memory T cells while preserving naive T cells and Tregs. These immunologic effects may serve to eliminate pathologic T cells in autoimmune diseases. TRIAL REGISTRATION. NCT02038764. FUNDING. Pfizer Inc.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::406708a6949f1f766cbebb2d99dd6f96Test
https://doi.org/10.1172/jci.insight.126054Test

المؤلفون: A. Dimitrios Colevas, Joshua Bloomstein, Rie von Eyben, Clint T. Allen, Vangipuram S. Rangan, Todd A. Aguilera, Albert C. Koong, Quynh-Thu Le, Dadi Jiang, Hongbin Cao, Christina S. Kong, Shirley Kwok, Amato J. Giaccia, Alan J. Korman, Sonya Agarwal, Rachel Liang, Dhanya Nambiar, Zemin Wang, Ravindra Uppaluri

المصدر: J Clin Invest

مصطلحات موضوعية: Adult, Male, 0301 basic medicine, Firearms, Galectin 1, Galectins, medicine.medical_treatment, T cell, T-Lymphocytes, Programmed Cell Death 1 Receptor, B7-H1 Antigen, 03 medical and health sciences, Mice, 0302 clinical medicine, Immune system, Downregulation and upregulation, Immune Tolerance, Medicine, Animals, Humans, Endothelium, Aged, Aged, 80 and over, business.industry, General Medicine, Immunotherapy, Middle Aged, Blockade, Mice, Inbred C57BL, Radiation therapy, carbohydrates (lipids), STAT1 Transcription Factor, 030104 developmental biology, medicine.anatomical_structure, Head and Neck Neoplasms, 030220 oncology & carcinogenesis, Galectin-1, Commentary, T cell migration, Cancer research, Female, business, Research Article

الوصف: Cancer immunotherapy and its budding effectiveness at improving patient outcomes has revitalized our hope to fight cancer in a logical and safe manner. Immunotherapeutic approaches to reengage the immune system have largely focused on reversing immune checkpoint inhibitor pathways, which suppress the antitumor response. Although these approaches have generated much excitement, they still lack absolute success. Interestingly, newly described host-tumor sugar chains (glycosylations) and glycosylation-binding proteins (lectins) play key roles in evading the immune system to determine cancer progression. In this issue of the JCI, Nambiar et al. used patient head and neck tumors and a mouse model system to investigate the role of galactose-binding lectin 1 (Gal1) in immunotherapy resistance. The authors demonstrated that Gal1 can affect immune checkpoint inhibitor therapy by increasing immune checkpoint molecules and immunosuppressive signaling in the tumor. Notably, these results suggest that targeting a tumor’s glycobiological state will improve treatment efficacy.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::10ae2195bd4106f7d6202d49886da83dTest
https://europepmc.org/articles/PMC6877340Test/

المؤلفون: Tasuku Honjo, Toyohiro Hirai, Yuichi Sakamori, Yasushi Okuno, Maryam Akrami, Fumihiko Matsuda, Ryusuke Hatae, Hiroaki Ozasa, Hironori Yoshida, Kazuhiro Sonomura, Kenji Chamoto, Kei Taneishi, Shuji Kawaguchi, Sidonia Fagarasan, Izuru Masuda, Young Hak Kim

المصدر: JCI Insight. 5

مصطلحات موضوعية: Adult, Male, 0301 basic medicine, Lung Neoplasms, Metabolite, medicine.medical_treatment, T cell, Programmed Cell Death 1 Receptor, 03 medical and health sciences, chemistry.chemical_compound, Antineoplastic Agents, Immunological, 0302 clinical medicine, Immune system, Cancer immunotherapy, Carcinoma, Non-Small-Cell Lung, Carnitine, Biomarkers, Tumor, Humans, Medicine, Prospective Studies, Beta oxidation, Aged, Aged, 80 and over, Glutathione Disulfide, business.industry, Hippurates, Microbiota, General Medicine, Middle Aged, Nivolumab, 030104 developmental biology, medicine.anatomical_structure, chemistry, 030220 oncology & carcinogenesis, Cancer research, Glutathione disulfide, Drug Therapy, Combination, Female, Immunotherapy, Clinical Medicine, Energy Metabolism, business, CD8

الوصف: BACKGROUND: Current clinical biomarkers for the programmed cell death 1 (PD-1) blockade therapy are insufficient because they rely only on the tumor properties, such as programmed cell death ligand 1 expression frequency and tumor mutation burden. Identifying reliable, responsive biomarkers based on the host immunity is necessary to improve the predictive values. METHODS: We investigated levels of plasma metabolites and T cell properties, including energy metabolism markers, in the blood of patients with non-small cell lung cancer before and after treatment with nivolumab (n = 55). Predictive values of combination markers statistically selected were evaluated by cross-validation and linear discriminant analysis on discovery and validation cohorts, respectively. Correlation between plasma metabolites and T cell markers was investigated. RESULTS: The 4 metabolites derived from the microbiome (hippuric acid), fatty acid oxidation (butyrylcarnitine), and redox (cystine and glutathione disulfide) provided high response probability (AUC = 0.91). Similarly, a combination of 4 T cell markers, those related to mitochondrial activation (PPARγ coactivator 1 expression and ROS), and the frequencies of CD8(+)PD-1(hi) and CD4(+) T cells demonstrated even higher prediction value (AUC = 0.96). Among the pool of selected markers, the 4 T cell markers were exclusively selected as the highest predictive combination, probably because of their linkage to the abovementioned metabolite markers. In a prospective validation set (n = 24), these 4 cellular markers showed a high accuracy rate for clinical responses of patients (AUC = 0.92). CONCLUSION: Combination of biomarkers reflecting host immune activity is quite valuable for responder prediction. FUNDING: AMED under grant numbers 18cm0106302h0003, 18gm0710012h0105, and 18lk1403006h0002; the Tang Prize Foundation; and JSPS KAKENHI grant numbers JP16H06149, 17K19593, and 19K17673.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a0f8b83c0a144f9febe31ec1f05c62abTest
https://doi.org/10.1172/jci.insight.133501Test

المؤلفون: Marco Klinger, Stefania Vetrano, Biagio Di Lorenzo, Michele Carvello, Anna Villa, Marita Bosticardo, Silvio Danese, Massimo Roncalli, Francesco Dieli, Antonino Spinelli, Elena Bruni, Ileana Bortolomai, Alessandra Roberto, Matteo Sacchi, Bruno Silva-Santos, Immo Prinz, Federico Colombo, Ferdinando Oriolo, Elena Lo Presti, Paola Spaggiari, Giovanni Cugini, Emanuela Marcenaro, Giovanni Colombo, Joanna Mikulak, Sarina Ravens, Serena Meraviglia, Domenico Mavilio, Silvia Della Bella

المساهمون: Mikulak, Joanna, Oriolo, Ferdinando, Bruni, Elena, Roberto, Alessandra, Colombo, Federico S, Villa, Anna, Bosticardo, Marita, Bortolomai, Ileana, Lo Presti, Elena, Meraviglia, Serena, Dieli, Francesco, Vetrano, Stefania, Danese, Silvio, Della Bella, Silvia, Carvello, Michele M, Sacchi, Matteo, Cugini, Giovanni, Colombo, Giovanni, Klinger, Marco, Spaggiari, Paola, Roncalli, Massimo, Prinz, Immo, Ravens, Sarina, di Lorenzo, Biagio, Marcenaro, Emanuela, Silva-Santos, Bruno, Spinelli, Antonino, Mavilio, Domenico

مصطلحات موضوعية: 0301 basic medicine, Male, Colorectal cancer, Immunotherapy, Adoptive, Mice, 0302 clinical medicine, Sex Hormone-Binding Globulin, Cytotoxic T cell, Antigens, Ly, Intestinal Mucosa, Intraepithelial Lymphocytes, Innate immunity, Aged, 80 and over, Gastroenterology, Age Factors, Receptors, Antigen, T-Cell, gamma-delta, General Medicine, Middle Aged, Phenotype, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Disease Progression, Female, Colorectal Neoplasms, Research Article, Adult, Colon, T cell, Immunology, T cells, Biology, digestive system, 03 medical and health sciences, Young Adult, Ileum, medicine, Animals, Humans, Aged, Neoplasm Staging, Tumor microenvironment, Innate immune system, Natural Cytotoxicity Triggering Receptor 1, medicine.disease, 030104 developmental biology, Cancer research, Intraepithelial lymphocyte, Homing (hematopoietic), T-Lymphocytes, Cytotoxic

الوصف: γδ T cells account for a large fraction of human intestinal intraepithelial lymphocytes (IELs) endowed with potent anti-tumor activities. However, little is known about their origin, phenotype and clinical relevance in colorectal cancer (CRC). To determine γδ IEL gut-specificity, homing and functions, γδ T cells were purified from human healthy blood, lymph nodes, liver, skin, intestine either disease-free or affected by CRC or generated from thymic precursors. The constitutive expression of NKp46 specifically identifies a new subset of cytotoxic Vδ1 T cells representing the largest fraction of gut-resident IELs. The ontogeny and gut-tropism of NKp46pos/Vδ1 IELs depends both on distinctive features of Vδ1 thymic precursors and gut-environmental factors. Either the constitutive presence of NKp46 on tissue-resident Vδ1 intestinal IELs or its induced-expression on IL-2/IL-15 activated Vδ1 thymocytes are associated with anti-tumor functions. Higher frequencies of NKp46pos/Vδ1 IELs in tumor-free specimens from CRC patients correlate with a lower risk of developing metastatic III/IV disease stages. Additionally, our in vitro settings reproducing CRC tumor-microenvironment inhibited the expansion of NKp46pos/Vδ1 cells from activated thymic precursors. These results parallel the very low frequencies of NKp46pos/Vδ1 IELs able to infiltrate CRC, thus providing new insights to either follow-up cancer progression or develop novel adoptive cellular therapies.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4b1e3fbd8fd94fdf6ed061ea76ae26ebTest
https://europepmc.org/articles/PMC6975269Test/

المؤلفون: Ravindra Uppaluri, Jochen H. Lorch, Alexander Frieden, Frank C. Kuo, Glenn J. Hanna, Megan E. Cavanaugh, Jonathan D. Schoenfeld, Patrick H. Lizotte, Robert I. Haddad, Nicole G. Chau, Laura E. MacConaill, Priyanka Shivdasani

المصدر: JCI Insight, Vol 3, Iss 4 (2018)

مصطلحات موضوعية: Male, 0301 basic medicine, Oncology, Biopsy, medicine.medical_treatment, DNA Mutational Analysis, Programmed Cell Death 1 Receptor, lcsh:Medicine, B7-H1 Antigen, Antineoplastic Agents, Immunological, 0302 clinical medicine, Mutation Rate, Genes, Tumor Suppressor, Prospective Studies, Frameshift Mutation, Prospective cohort study, Aged, 80 and over, General Medicine, Middle Aged, Prognosis, Neoadjuvant Therapy, Treatment Outcome, medicine.anatomical_structure, Head and Neck Neoplasms, 030220 oncology & carcinogenesis, Female, Research Article, Adult, medicine.medical_specialty, T cell, Frameshift mutation, Young Adult, 03 medical and health sciences, Internal medicine, Biomarkers, Tumor, Genetics, medicine, Humans, Survival analysis, Aged, Chemotherapy, Squamous Cell Carcinoma of Head and Neck, business.industry, lcsh:R, Head and neck cancer, Immunotherapy, medicine.disease, Survival Analysis, Otorhinolaryngologic Surgical Procedures, 030104 developmental biology, Drug Resistance, Neoplasm, business, CD8

الوصف: Programmed cell death protein 1 (PD-1) inhibitors have efficacy in treating squamous cell carcinoma of the head and neck (SCCHN), but objective response rates are low. PD-1 ligand (PD-L1) expression alone is not considered a robust predictor of response and additional biomarkers are needed. This 3-year observational cohort followed 126 SCCHN patients treated with anti–PD-1/L1 therapy. Prior to treatment, 81 (64%) had targeted massively parallel tumor sequencing. Of these, 42 (52%) underwent fluorescence-activated cell sorting and PD-L1 immunohistochemistry for tumor immunoprofiling. Six (5%) complete responses (CRs) and 11 (9%) partial responses (PRs) were observed. Those treated with prior chemotherapy (98, 78%) versus only surgery and/or radiation had longer overall survival (OS) (10 vs. 3 months, P = 0.02). Smokers had a higher total mutational burden (TMB) (P = 0.01). Virus-positive patients had a lower TMB (P < 0.01) and improved OS (P = 0.02). Among virus-negative responders, NOTCH1 and SMARCA4 were more frequently mutated and frameshift events in tumor suppressor genes occurred more frequently (P = 0.03). Higher TMB and CD8+ T cell infiltrates predicted anti–PD-1/L1 benefit (P < 0.01, P < 0.01, respectively) among virus-negative tumors. TIM-3/LAG-3 coexpression with PD-1 was higher on T cells among nonresponders (P = 0.03 and 0.02, respectively). Somatic frameshift events in tumor suppressor genes and higher TMB among virus-negative SCCHN tumors predict anti–PD-1/L1 response.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7d14182187ffb2939faf895230365f8bTest
https://doi.org/10.1172/jci.insight.98811Test

المؤلفون: Partheepan Narendran, Kesley Attridge, Lucy S. K. Walker, Chun Jing Wang, Lukasz Wardzinski, Louise E. Clough, Sapna Patel, Frank Heuts, Rupert Kenefeck, Tauseef Kapadi, Miranda Rosenthal, Masahiro Ono, David M. Sansom, Alexandros Kogimtzis

المصدر: Journal of Clinical Investigation. 125:292-303

مصطلحات موضوعية: Adult, Male, Receptors, CXCR5, Interleukin 2, Cellular differentiation, T cell, Mice, Transgenic, Human leukocyte antigen, Biology, Lymphocyte Activation, Autoantigens, 03 medical and health sciences, Interleukin 21, 0302 clinical medicine, medicine, Animals, Humans, Cytotoxic T cell, IL-2 receptor, Pancreas, 030304 developmental biology, Mice, Inbred BALB C, 0303 health sciences, Interleukins, T-Lymphocytes, Helper-Inducer, General Medicine, Up-Regulation, Diabetes Mellitus, Type 1, medicine.anatomical_structure, Case-Control Studies, T cell differentiation, Immunology, Interleukin-2, Female, Lymph Nodes, Transcriptome, Immunologic Memory, Research Article, 030215 immunology, medicine.drug

الوصف: The strong genetic association between particular HLA alleles and type 1 diabetes (T1D) indicates a key role for CD4+ T cells in disease; however, the differentiation state of the responsible T cells is unclear. T cell differentiation originally was considered a dichotomy between Th1 and Th2 cells, with Th1 cells deemed culpable for autoimmune islet destruction. Now, multiple additional T cell differentiation fates are recognized with distinct roles. Here, we used a transgenic mouse model of diabetes to probe the gene expression profile of islet-specific T cells by microarray and identified a clear follicular helper T (Tfh) cell differentiation signature. Introduction of T cells with a Tfh cell phenotype from diabetic animals efficiently transferred diabetes to recipient animals. Furthermore, memory T cells from patients with T1D expressed elevated levels of Tfh cell markers, including CXCR5, ICOS, PDCD1, BCL6, and IL21. Defects in the IL-2 pathway are associated with T1D, and IL-2 inhibits Tfh cell differentiation in mice. Consistent with these previous observations, we found that IL-2 inhibited human Tfh cell differentiation and identified a relationship between IL-2 sensitivity in T cells from patients with T1D and acquisition of a Tfh cell phenotype. Together, these findings identify a Tfh cell signature in autoimmune diabetes and suggest that this population could be used as a biomarker and potentially targeted for T1D interventions.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::cd17746e98f6767d1745f32ff8ac3631Test
https://doi.org/10.1172/jci76238Test