The chromatin and single-cell transcriptional landscapes of CD4 T cells in inflammatory bowel disease link risk loci with a proinflammatory Th17 cell population.

Autor:	Medina TS; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.; International Research Center, A.C. Camargo Cancer Center, São Paulo, Brazil., Murison A; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada., Smith M; Division of Gastroenterology, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada., Kinker GS; International Research Center, A.C. Camargo Cancer Center, São Paulo, Brazil., Chakravarthy A; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada., Vitiello GAF; International Research Center, A.C. Camargo Cancer Center, São Paulo, Brazil., Turpin W; Division of Gastroenterology, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada., Shen SY; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada., Yau HL; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada., Sarmento OF; Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States., Faubion W; Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States., Lupien M; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada., Silverberg MS; Division of Gastroenterology, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada., Arrowsmith CH; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.; Structural Genomics Consortium, University of Toronto, Toronto, ON, Canada., De Carvalho DD; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2023 Aug 03; Vol. 14, pp. 1161901. Date of Electronic Publication: 2023 Aug 03 (Print Publication: 2023).
DOI:	10.3389/fimmu.2023.1161901
Abstrakt:	Introduction: The imbalance between Th17 and regulatory T cells in inflammatory bowel diseases (IBD) promotes intestinal epithelial cell damage. In this scenario, T helper cell lineage commitment is accompanied by dynamic changes to the chromatin that facilitate or repress gene expression. Methods: Here, we characterized the chromatin landscape and heterogeneity of intestinal and peripheral CD4 T cellsfrom IBD patients using in house ATAC-Seq and single cell RNA-Seq libraries. Results: We show that chromatin accessibility profiles of CD4 T cells from inflamed intestinal biopsies relate to genes associated with a network of inflammatory processes. After integrating the chromatin profiles of tissue-derived CD4 T cells and in-vitro polarized CD4 T cell subpopulations, we found that the chromatin accessibility changes of CD4 T cells were associated with a higher predominance of pathogenic Th17 cells (pTh17 cells) in inflamed biopsies. In addition, IBD risk loci in CD4 T cells were colocalized with accessible chromatin changes near pTh17-related genes, as shown in intronic STAT3 and IL23R regions enriched in areas of active intestinal inflammation. Moreover, single cell RNA-Seq analysis revealed a population of pTh17 cells that co-expresses Th1 and cytotoxic transcriptional programs associated with IBD severity. Discussion: Altogether, we show that cytotoxic pTh17 cells were specifically associated with IBD genetic variants and linked to intestinal inflammation of IBD patients. Competing Interests: DC reports research support from Pfizer outside of the submitted work and is a co-founder, shareholder and CSO of Adela, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2023 Medina, Murison, Smith, Kinker, Chakravarthy, Vitiello, Turpin, Shen, Yau, Sarmento, Faubion, Lupien, Silverberg, Arrowsmith and De Carvalho.)
Databáze:	MEDLINE
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