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Journal ArticleDOI

Pathogenic T Cells in Celiac Disease Change Phenotype on Gluten Challenge: Implications for T-Cell-Directed Therapies

TL;DR: In this article, a 3-day gluten challenge was used to study the phenotype of gluten-specific CD4+ T cells in patients with celiac disease (CeD) and other autoimmune conditions.
Abstract: Gluten-specific CD4+ T cells being drivers of celiac disease (CeD) are obvious targets for immunotherapy. Little is known about how cell markers harnessed for T-cell-directed therapy can change with time and upon activation in CeD and other autoimmune conditions. In-depth characterization of gluten-specific CD4+ T cells and CeD-associated (CD38+ and CD103+ ) CD8+ and γδ+ T cells in blood of treated CeD patients undergoing a 3 day gluten challenge is reported. The phenotypic profile of gluten-specific cells changes profoundly with gluten exposure and the cells adopt the profile of gluten-specific cells in untreated disease (CD147+ , CD70+ , programmed cell death protein 1 (PD-1)+ , inducible T-cell costimulator (ICOS)+ , CD28+ , CD95+ , CD38+ , and CD161+ ), yet with some markers being unique for day 6 cells (C-X-C chemokine receptor type 6 (CXCR6), CD132, and CD147) and with integrin α4β7, C-C motif chemokine receptor 9 (CCR9), and CXCR3 being expressed stably at baseline and day 6. Among gluten-specific CD4+ T cells, 52% are CXCR5+ at baseline, perhaps indicative of germinal-center reactions, while on day 6 all are CXCR5- . Strikingly, the phenotypic profile of gluten-specific CD4+ T cells on day 6 largely overlaps with that of CeD-associated (CD38+ and CD103+ ) CD8+ and γδ+ T cells. The antigen-induced shift in phenotype of CD4+ T cells being shared with other disease-associated T cells is relevant for development of T-cell-directed therapies.
Citations
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Journal ArticleDOI
25 Jul 2022-Gut
TL;DR: Demonstration that lymphomas complicating CD arise from IEL that have acquired gain-of-function JAK1 or STAT3 mutations stresses the key role of this pathway and explains how gluten-driven chronic inflammation may promote this rare but most severe complication.
Abstract: Coeliac disease (CD) is a frequent immune enteropathy induced by gluten in genetically predisposed individuals. Its pathogenesis has been extensively studied and CD has emerged as a model disease to decipher how the interplay between environmental and genetic factors can predispose to autoimmunity and promote lymphomagenesis. The keystone event is the activation of a gluten-specific immune response that is driven by molecular interactions between gluten, the indispensable environmental factor, HLA-DQ2/8, the main predisposing genetic factor and transglutaminase 2, the CD-specific autoantigen. The antigluten response is however not sufficient to induce epithelial damage which requires the activation of cytotoxic CD8+ intraepithelial lymphocytes (IEL). In a plausible scenario, cooperation between cytokines released by gluten-specific CD4+ T cells and interleukin-15 produced in excess in the coeliac gut, licenses the autoimmune-like attack of the gut epithelium, likely via sustained activation of the Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathway in IEL. Demonstration that lymphomas complicating CD arise from IEL that have acquired gain-of-function JAK1 or STAT3 mutations stresses the key role of this pathway and explains how gluten-driven chronic inflammation may promote this rare but most severe complication. If our understanding of CD pathogenesis has considerably progressed, several questions and challenges remain. One unsolved question concerns the considerable variability in disease penetrance, severity and presentation, pointing to the role of additional genetic and environmental factors that remain however uneasy to untangle and hierarchize. A current challenge is to transfer the considerable mechanistic insight gained into CD pathogenesis into benefits for the patients, notably to alleviate the gluten-free diet, a burden for many patients.

9 citations

Journal ArticleDOI
TL;DR: Current understanding of the immunobiology of celiac disease is presented, with mechanistic insights into how the disease-predisposing HLA-DQ molecules, via presentation of posttranslationally modified gluten peptides, are connected to the generation of these autoantibodies.
Abstract: Among human leukocyte antigen (HLA)-associated disorders, celiac disease has an immunopathogenesis that is particularly well understood. The condition is characterized by hypersensitivity to cereal gluten proteins, and the disease lesion is localized in the gut. Still, the diagnosis can be made by detection of highly disease-specific autoantibodies to transglutaminase 2 in the blood. We now have mechanistic insights into how the disease-predisposing HLA-DQ molecules, via presentation of posttranslationally modified gluten peptides, are connected to the generation of these autoantibodies. This review presents our current understanding of the immunobiology of this common disorder that is positioned in the border zone between food hypersensitivity and autoimmunity. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 18 is January 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

8 citations

Journal ArticleDOI
TL;DR: The feasibility to isolate antigen‐specific CD4+ T cells by the sole use of phenotypic markers in CeD outlines a potential avenue for characterizing disease‐driving CD4 + T cells in autoimmune conditions.
Abstract: The pathogenic immune response in celiac disease (CeD) is orchestrated by phenotypically distinct CD4+ T cells that recognize gluten epitopes in the context of disease‐associated HLA‐DQ allotypes. Cells with the same distinct phenotype, but with elusive specificities, are increased across multiple autoimmune conditions. Here, whether sorting of T cells based on their distinct phenotype (Tphe cells) yields gluten‐reactive cells in CeD is tested. The method′s efficiency is benchmarked by parallel isolation of gluten‐reactive T cells (Ttet cells), using HLA‐DQ:gluten peptide tetramers. From gut biopsies of 12 untreated HLA‐DQ2.5+ CeD patients, Ttet+/Tphe+, Ttet−/Tphe+, and Ttet−/Tphe− cells are sorted for single‐cell T‐cell receptor (TCR)‐sequencing (n = 8) and T‐cell clone (TCC)‐generation (n = 5). The generated TCCs are TCR sequenced and tested for their reactivity against deamidated gluten. Gluten‐reactivity is observed in 91.2% of Ttet+/Tphe+ TCCs, 65.3% of Ttet−/Tphe+ TCCs and 0% of Ttet−/Tphe− TCCs. TCR sequencing reveals clonal expansion and sequence sharing across patients, features reflecting antigen‐driven responses. The feasibility to isolate antigen‐specific CD4+ T cells by the sole use of phenotypic markers in CeD outlines a potential avenue for characterizing disease‐driving CD4+ T cells in autoimmune conditions.

6 citations

Journal ArticleDOI
TL;DR: The role and clinical effects of CD4+ T cells directed against deamidated gluten in the context of an "adaptive immune paradigm" are reviewed in this paper, where alternative hypotheses of gluten toxicity are discussed and contrasted.
Abstract: Introduction Recent patient studies have shown that gluten-free diet is less effective in treating celiac disease than previously believed, and additionally patients remain vulnerable to gluten-induced acute symptoms and systemic cytokine release. Safe and effective pharmacological adjuncts to gluten-free diet are in preclinical and clinical development. Clear understanding of the pathogenesis of celiac disease is critical for drug target identification, establishing efficacy endpoints and to develop non-invasive biomarkers suitable to monitor and potentially diagnose celiac disease. Areas covered The role and clinical effects of CD4+ T cells directed against deamidated gluten in the context of an "adaptive immune paradigm" are reviewed. Alternative hypotheses of gluten toxicity are discussed and contrasted. In the context of recent patient studies, implications of the adaptive immune paradigm for future strategies to prevent, diagnose, and treat celiac disease are outlined. Expert opinion Effective therapeutics for celiac disease are likely to be approved and necessitate a variety of new clinical instruments and tests to stratify patient need, monitor remission, and confirm diagnosis in uncertain cases. Sensitive assessments of CD4+ T cells specific for deamidated gluten are likely to play a central role in clinical management, and to facilitate research and pharmaceutical development.

4 citations

Journal ArticleDOI
Samira Aziz1
TL;DR: The role and clinical effects of CD4+ T cells directed against deamidated gluten in the context of an "adaptive immune paradigm" are reviewed in this article , where the implications of the adaptive immune paradigm for future strategies to prevent, diagnose, and treat celiac disease are outlined.
Abstract: Recent patient studies have shown that gluten-free diet is less effective in treating celiac disease than previously believed, and additionally patients remain vulnerable to gluten-induced acute symptoms and systemic cytokine release. Safe and effective pharmacological adjuncts to gluten-free diet are in preclinical and clinical development. Clear understanding of the pathogenesis of celiac disease is critical for drug target identification, establishing efficacy endpoints and to develop noninvasive biomarkers suitable to monitor and potentially diagnose celiac disease.The role and clinical effects of CD4+ T cells directed against deamidated gluten in the context of an 'adaptive immune paradigm' are reviewed. Alternative hypotheses of gluten toxicity are discussed and contrasted. In the context of recent patient studies, implications of the adaptive immune paradigm for future strategies to prevent, diagnose, and treat celiac disease are outlined.Effective therapeutics for celiac disease are likely to be approved and necessitate a variety of new clinical instruments and tests to stratify patient need, monitor remission, and confirm diagnosis in uncertain cases. Sensitive assessments of CD4+ T cells specific for deamidated gluten are likely to play a central role in clinical management, and to facilitate research and pharmaceutical development.

4 citations

References
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Journal ArticleDOI
TL;DR: Comparing the performance of UMAP with five other tools, it is found that UMAP provides the fastest run times, highest reproducibility and the most meaningful organization of cell clusters.
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Journal ArticleDOI
01 Sep 2004-Immunity
TL;DR: It is shown that, under conditions of dysregulated IL15 expression in vivo in patients with celiac disease and in vitro in healthy individuals, multiple steps of the NKG2D/DAP10 signaling pathway leading to ERK and JNK activation are coordinately primed to activate direct cytolytic function independent of TCR specificity in effector CD8 T cells.

800 citations

Journal ArticleDOI
02 Feb 2017-Nature
TL;DR: Using multidimensional cytometry, transcriptomics, and functional assays, a population of PD-1hiCXCR5− ‘peripheral helper’ T (TPH) cells that express factors enabling B-cell help, including IL-21, CXCL13, ICOS, and MAF are defined.
Abstract: CD4+ T cells are central mediators of autoimmune pathology; however, defining their key effector functions in specific autoimmune diseases remains challenging. Pathogenic CD4+ T cells within affected tissues may be identified by expression of markers of recent activation. Here we use mass cytometry to analyse activated T cells in joint tissue from patients with rheumatoid arthritis, a chronic immune-mediated arthritis that affects up to 1% of the population. This approach revealed a markedly expanded population of PD-1hiCXCR5-CD4+ T cells in synovium of patients with rheumatoid arthritis. However, these cells are not exhausted, despite high PD-1 expression. Rather, using multidimensional cytometry, transcriptomics, and functional assays, we define a population of PD-1hiCXCR5- 'peripheral helper' T (TPH) cells that express factors enabling B-cell help, including IL-21, CXCL13, ICOS, and MAF. Like PD-1hiCXCR5+ T follicular helper cells, TPH cells induce plasma cell differentiation in vitro through IL-21 secretion and SLAMF5 interaction (refs 3, 4). However, global transcriptomics highlight differences between TPH cells and T follicular helper cells, including altered expression of BCL6 and BLIMP1 and unique expression of chemokine receptors that direct migration to inflamed sites, such as CCR2, CX3CR1, and CCR5, in TPH cells. TPH cells appear to be uniquely poised to promote B-cell responses and antibody production within pathologically inflamed non-lymphoid tissues.

697 citations

Journal ArticleDOI
TL;DR: The coexpression of CD49b and LAG-3 enables the isolation of highly suppressive human Tr 1 cells from in vitro anergized cultures and allows the tracking of Tr1 cells in the peripheral blood of subjects who developed tolerance after allogeneic hematopoietic stem cell transplantation.
Abstract: CD4(+) type 1 T regulatory (Tr1) cells are induced in the periphery and have a pivotal role in promoting and maintaining tolerance. The absence of surface markers that uniquely identify Tr1 cells has limited their study and clinical applications. By gene expression profiling of human Tr1 cell clones, we identified the surface markers CD49b and lymphocyte activation gene 3 (LAG-3) as being stably and selectively coexpressed on mouse and human Tr1 cells. We showed the specificity of these markers in mouse models of intestinal inflammation and helminth infection and in the peripheral blood of healthy volunteers. The coexpression of CD49b and LAG-3 enables the isolation of highly suppressive human Tr1 cells from in vitro anergized cultures and allows the tracking of Tr1 cells in the peripheral blood of subjects who developed tolerance after allogeneic hematopoietic stem cell transplantation. The use of these markers makes it feasible to track Tr1 cells in vivo and purify Tr1 cells for cell therapy to induce or restore tolerance in subjects with immune-mediated diseases.

676 citations

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