The chromatin and single-cell transcriptional landscapes of CD4 T cells in inflammatory bowel disease link risk loci with a proinflammatory Th17 cell population
IntroductionThe 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. MethodsHere...
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| Format: | Article |
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Frontiers Media S.A.
2023-08-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1161901/full |
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| author | Tiago S. Medina Tiago S. Medina Alex Murison Michelle Smith Gabriela S. Kinker Ankur Chakravarthy Glauco A. F. Vitiello Williams Turpin Shu Yi Shen Helen L. Yau Helen L. Yau Olga F. Sarmento William Faubion Mathieu Lupien Mathieu Lupien Mark S. Silverberg Cheryl H. Arrowsmith Cheryl H. Arrowsmith Cheryl H. Arrowsmith Daniel D. De Carvalho Daniel D. De Carvalho |
| author_facet | Tiago S. Medina Tiago S. Medina Alex Murison Michelle Smith Gabriela S. Kinker Ankur Chakravarthy Glauco A. F. Vitiello Williams Turpin Shu Yi Shen Helen L. Yau Helen L. Yau Olga F. Sarmento William Faubion Mathieu Lupien Mathieu Lupien Mark S. Silverberg Cheryl H. Arrowsmith Cheryl H. Arrowsmith Cheryl H. Arrowsmith Daniel D. De Carvalho Daniel D. De Carvalho |
| author_sort | Tiago S. Medina |
| collection | DOAJ |
| description | IntroductionThe 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. MethodsHere, 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. ResultsWe 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. DiscussionAltogether, we show that cytotoxic pTh17 cells were specifically associated with IBD genetic variants and linked to intestinal inflammation of IBD patients. |
| first_indexed | 2024-03-12T17:42:33Z |
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| id | doaj.art-48032f330d2f4012b81f6e5ecfa9adc0 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-12T17:42:33Z |
| publishDate | 2023-08-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj.art-48032f330d2f4012b81f6e5ecfa9adc02023-08-04T02:36:31ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-08-011410.3389/fimmu.2023.11619011161901The chromatin and single-cell transcriptional landscapes of CD4 T cells in inflammatory bowel disease link risk loci with a proinflammatory Th17 cell populationTiago S. Medina0Tiago S. Medina1Alex Murison2Michelle Smith3Gabriela S. Kinker4Ankur Chakravarthy5Glauco A. F. Vitiello6Williams Turpin7Shu Yi Shen8Helen L. Yau9Helen L. Yau10Olga F. Sarmento11William Faubion12Mathieu Lupien13Mathieu Lupien14Mark S. Silverberg15Cheryl H. Arrowsmith16Cheryl H. Arrowsmith17Cheryl H. Arrowsmith18Daniel D. De Carvalho19Daniel D. De Carvalho20Princess Margaret Cancer Centre, University Health Network, Toronto, ON, CanadaInternational Research Center, A.C. Camargo Cancer Center, São Paulo, BrazilPrincess Margaret Cancer Centre, University Health Network, Toronto, ON, CanadaDivision of Gastroenterology, Mount Sinai Hospital, University of Toronto, Toronto, ON, CanadaInternational Research Center, A.C. Camargo Cancer Center, São Paulo, BrazilPrincess Margaret Cancer Centre, University Health Network, Toronto, ON, CanadaInternational Research Center, A.C. Camargo Cancer Center, São Paulo, BrazilDivision of Gastroenterology, Mount Sinai Hospital, University of Toronto, Toronto, ON, CanadaPrincess Margaret Cancer Centre, University Health Network, Toronto, ON, CanadaPrincess Margaret Cancer Centre, University Health Network, Toronto, ON, CanadaDepartment of Medical Biophysics, University of Toronto, Toronto, ON, CanadaDivision of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United StatesDivision of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United StatesPrincess Margaret Cancer Centre, University Health Network, Toronto, ON, CanadaDepartment of Medical Biophysics, University of Toronto, Toronto, ON, CanadaDivision of Gastroenterology, Mount Sinai Hospital, University of Toronto, Toronto, ON, CanadaPrincess Margaret Cancer Centre, University Health Network, Toronto, ON, CanadaDepartment of Medical Biophysics, University of Toronto, Toronto, ON, CanadaStructural Genomics Consortium, University of Toronto, Toronto, ON, CanadaPrincess Margaret Cancer Centre, University Health Network, Toronto, ON, CanadaDepartment of Medical Biophysics, University of Toronto, Toronto, ON, CanadaIntroductionThe 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. MethodsHere, 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. ResultsWe 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. DiscussionAltogether, we show that cytotoxic pTh17 cells were specifically associated with IBD genetic variants and linked to intestinal inflammation of IBD patients.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1161901/fullinflammatory bowel disease (IBD)CD4 T cellsgenetic variantspathogenic (p)Th17 cellscytotoxicityCrohn's disease |
| spellingShingle | Tiago S. Medina Tiago S. Medina Alex Murison Michelle Smith Gabriela S. Kinker Ankur Chakravarthy Glauco A. F. Vitiello Williams Turpin Shu Yi Shen Helen L. Yau Helen L. Yau Olga F. Sarmento William Faubion Mathieu Lupien Mathieu Lupien Mark S. Silverberg Cheryl H. Arrowsmith Cheryl H. Arrowsmith Cheryl H. Arrowsmith Daniel D. De Carvalho Daniel D. De Carvalho The chromatin and single-cell transcriptional landscapes of CD4 T cells in inflammatory bowel disease link risk loci with a proinflammatory Th17 cell population Frontiers in Immunology inflammatory bowel disease (IBD) CD4 T cells genetic variants pathogenic (p)Th17 cells cytotoxicity Crohn's disease |
| title | The chromatin and single-cell transcriptional landscapes of CD4 T cells in inflammatory bowel disease link risk loci with a proinflammatory Th17 cell population |
| title_full | The chromatin and single-cell transcriptional landscapes of CD4 T cells in inflammatory bowel disease link risk loci with a proinflammatory Th17 cell population |
| title_fullStr | The chromatin and single-cell transcriptional landscapes of CD4 T cells in inflammatory bowel disease link risk loci with a proinflammatory Th17 cell population |
| title_full_unstemmed | The chromatin and single-cell transcriptional landscapes of CD4 T cells in inflammatory bowel disease link risk loci with a proinflammatory Th17 cell population |
| title_short | The chromatin and single-cell transcriptional landscapes of CD4 T cells in inflammatory bowel disease link risk loci with a proinflammatory Th17 cell population |
| title_sort | chromatin and single cell transcriptional landscapes of cd4 t cells in inflammatory bowel disease link risk loci with a proinflammatory th17 cell population |
| topic | inflammatory bowel disease (IBD) CD4 T cells genetic variants pathogenic (p)Th17 cells cytotoxicity Crohn's disease |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1161901/full |
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