Celiac disease (CD) is a highly prevalent 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 with different celiac disease states and controls. Untreated, active CD (ACD) and potential CD (PCD) 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 (GFD) 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. Following gluten ingestion, both αβ and γδ T cell clones from this memory population of T-IELs circulated systemically with gluten-specific CD4+ T cells and assumed a cytotoxic and activating NKR-expressing phenotype. In patient-derived organoid (PDO) model of CD, gluten exposure induced the presence of this cytotoxic, NKR-expressing population exclusively in PDOs generated from CD patients.
The increased abundance of cytotoxic, NKR-expressing T-IELs following gluten exposure corresponded to histologic observations of altered organoid morphology including degenerated organoid structures and the presence of infiltrating immune cells co-localized with apoptotic epithelial cells. Collectively, these findings suggest that these cytotoxic, NKR-expressing T cells in CD are rapidly mobilized in parallel with gluten-specific CD4+ T cells following gluten ingestion to mediate the destruction of intestinal epithelial cells in CD.
| Identifer | oai:union.ndltd.org:columbia.edu/oai:academiccommons.columbia.edu:10.7916/ew9s-9j46 |
| Date | January 2023 |
| Creators | Kornberg, Adam Elliott |
| Source Sets | Columbia University |
| Language | English |
| Detected Language | English |
| Type | Theses |
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