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Single-cell T-cell receptor sequencing of intraepithelial gammadelta T-cells in celiac disease

ABSTRACT: Single-cell paired TCR sequencing of intraepithelial ÃŽÂ³ÃŽÂ´ T-cells in gluten-free diet treated and untreated celiac disease patients and in controls. (Paired end, amplicon sequencing).

PROVIDER: EGAS00001003897 | EGA |

REPOSITORIES: EGA

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Single-cell T-cell receptor sequencing of intraepithelial CD8+ ÃŽÂ±ÃŽÂ² T-cells in celiac disease

Project description:Single-cell paired TCR sequencing of intraepithelial CD8+ ÃŽÂ±ÃŽÂ² T-cells in gluten-free diet treated and untreated celiac disease patients and in controls. (Paired end, amplicon sequencing).

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Chronic inflammation permanently reshapes tissue-resident immunity in celiac disease

Project description:Chronic inflammation driven by persistent antigenic challenge with dietary gluten permanently reshapes the tissue-resident TCRgd+ intraepithelial lymphocyte compartment in patients with celiac disease.

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Reprogramming of CTLs into natural killer-like cells in celiac disease

Project description:Celiac disease is an intestinal inflammatory disorder induced by dietary gluten in genetically susceptible individuals. The mechanisms underlying the massive expansion of interferon g–producing intraepithelial cytotoxic T lymphocytes (CTLs) and the destruction of the epithelial cells lining the small intestine of celiac patients have remained elusive. We report massive oligoclonal expansions of intraepithelial CTLs that exhibit a profound genetic reprogramming of natural killer (NK) functions. These CTLs aberrantly expressed cytolytic NK lineage receptors, such as NKG2C, NKp44, and NKp46, which associate with adaptor molecules bearing immunoreceptor tyrosine-based activation motifs and induce ZAP-70 phosphorylation, cytokine secretion, and proliferation independently of T cell receptor signaling. This NK transformation of CTLs may underlie both the self-perpetuating, gluten-independent tissue damage and the uncontrolled CTL expansion leading to malignant lymphomas in severe forms of celiac disease. Because similar changes were detected in a subset of CTLs from cytomegalovirus-seropositive patients, we suggest that a stepwise transformation of CTLs into NK-like cells may underlie immunopathology in various chronic infectious and inflammatory diseases. Keywords: NKG2C; LAK; CTL; NK receptor; IEL; Mucosal Immunity; Celiac Disease

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Gluten induces rapid reprogramming of natural memory αβ and γδ intraepithelial T cells to induce cytotoxicity in celiac disease

Project description:Celiac disease (CD) is an autoimmune disease in which intestinal inflammation is induced by dietary gluten. The means through which gluten-specific CD4+T cell activation culminates in intraepithelial T cell (T-IEL)–mediated intestinal damage remain unclear. Here, we performed multiplexed single-cell analysis of intestinal and gluten-induced peripheral blood T cells from patients in different CD states and healthy controls. Untreated, active, and potential CD were associated with an enrichment of activated intestinal T cell populations, including CD4+follicular T helper (TFH) cells, regulatory T cells (Tregs), and natural CD8+αβ and γδ T-IELs. Natural CD8+αβ and γδ T-IELs expressing activating natural killer cell receptors (NKRs) exhibited a distinct TCR repertoire in CD and persisted in patients on a gluten-free diet without intestinal inflammation. Our data further show that NKR-expressing cytotoxic cells, which appear to mediate intestinal damage in CD, arise from a distinct NKR-expressing memory population of T-IELs. After gluten ingestion, both αβ and γδ T cell clones from this memory population of T-IELs circulated systemically along with gluten-specific CD4+T cells and assumed a cytotoxic and activating NKR-expressing phenotype. Collectively, these findings suggest that cytotoxic T cells in CD are rapidly mobilized in parallel with gluten-specific CD4+T cells after gluten ingestion.

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2009-06-01 | E-MEXP-1823 | biostudies-arrayexpress

Single cell transcriptomic analysis of the immune cell compartment in the human small intestine and in Celiac disease

Project description:Celiac disease is an autoimmune disorder in which ingestion of dietary gluten triggers an immune reaction in the small intestine leading to destruction of the lining epithelium. Current treatment focusses on lifelong adherence to a gluten-free diet. Gluten-specific CD4+ T cells and cytotoxic intraepithelial CD8+ T cells have been proposed to be central in disease pathogenesis. Here we use unbiased single-cell RNA-sequencing and explore the heterogeneity of CD45+ immune cells in the human small intestine. We show altered myeloid cell transcriptomes present in active celiac lesions. CD4+ and CD8+ T cells transcriptomes show extensive changes and we define a natural intraepithelial lymphocyte population that is reduced in celiac disease. We show that the immune landscape in Celiac patients on a gluten-free diet is only partially restored compared to control samples. Altogether, we provide a single cell transcriptome resource that can inform the immune landscape of the small intestine during Celiac disease.

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Project description:Celiac disease is a chronic immune-mediated disorder with an important genetic component. To date, there are 57 independent association signals from 39 non-HLA loci, and a total of 66 candidate genes have been proposed. We aimed to scrutinize the functional implication of 45 of those genes by analyzing their expression in the disease tissue of celiac patients (at diagnosis/treatment) compared to non-celiac controls. The sample set consisted of 15 CD children at diagnosis (on a gluten-containing diet, with CD associated antibodies, atrophy of intestinal villi and crypt hyperplasia), and the same patients in remission after being treated with GFD for >2 years (asymptomatic, antibody negative, and normalized intestinal epithelium at that time), plus 15 tissue samples from non-celiac individuals not suffering from inflammation at the time of endoscopy used as controls

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40380f5a-350e-44bc-9f8f-97bc9f527d4c - samples

Project description:Paired T-cell receptor sequences sequenced from single cells, from intraepithalial CD8+ ÃŽÂ±ÃŽÂ² T-cells. Sequences are from from untreated and treated (on a gluten-free diet) celiac disease patients and controls.

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