Research ResourcesINFLAMMATORY BOWEL DISEASE

Heterogeneity and clonal relationships of adaptive immune cells in ulcerative colitis revealed by single-cell analyses

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Science Immunology  21 Aug 2020:
Vol. 5, Issue 50, eabb4432
DOI: 10.1126/sciimmunol.abb4432

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Profiles of rogue gut lymphocytes

Dysregulated human gut B and T lymphocytes contribute to the immunopathogenesis of ulcerative colitis (UC), a type of inflammatory bowel disease (IBD) characterized by mucosal damage in the colon. Boland et al. probed the immunologic perturbations associated with active UC by sequencing mRNA and clonal antigen receptors from individual CD45+ cells isolated from rectal biopsies or blood of patients and healthy controls. The resulting single-cell sequencing resource revealed heterogeneity among tissue-resident memory T cells (TRM) in UC, including expansion of an inflammatory CD8+ TRM subset expressing the Eomesodermin transcription factor. The identification of this TRM population and other disease-associated T and B cell subsets provides a platform for future functional studies addressing how these subsets conspire to trigger chronic mucosal injury in UC.

Abstract

Inflammatory bowel disease (IBD) encompasses a spectrum of gastrointestinal disorders driven by dysregulated immune responses against gut microbiota. We integrated single-cell RNA and antigen receptor sequencing to elucidate key components, cellular states, and clonal relationships of the peripheral and gastrointestinal mucosal immune systems in health and ulcerative colitis (UC). UC was associated with an increase in IgG1+ plasma cells in colonic tissue, increased colonic regulatory T cells characterized by elevated expression of the transcription factor ZEB2, and an enrichment of a γδ T cell subset in the peripheral blood. Moreover, we observed heterogeneity in CD8+ tissue-resident memory T (TRM) cells in colonic tissue, with four transcriptionally distinct states of differentiation observed across health and disease. In the setting of UC, there was a marked shift of clonally related CD8+ TRM cells toward an inflammatory state, mediated, in part, by increased expression of the T-box transcription factor Eomesodermin. Together, these results provide a detailed atlas of transcriptional changes occurring in adaptive immune cells in the context of UC and suggest a role for CD8+ TRM cells in IBD.

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