The chromatin and single-cell transcriptional landscapes of CD4 T cells in inflammatory bowel disease link risk loci with a proinflammatory Th17 cell population.
CD4 T cells
Crohn's disease
Ulcerative colitis
cytotoxicity
genetic variants
inflammatory bowel disease (IBD)
pathogenic (p)Th17 cells
Journal
Frontiers in immunology
ISSN: 1664-3224
Titre abrégé: Front Immunol
Pays: Switzerland
ID NLM: 101560960
Informations de publication
Date de publication:
2023
2023
Historique:
received:
08
02
2023
accepted:
03
07
2023
medline:
22
8
2023
pubmed:
21
8
2023
entrez:
21
8
2023
Statut:
epublish
Résumé
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. 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. 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. Altogether, we show that cytotoxic pTh17 cells were specifically associated with IBD genetic variants and linked to intestinal inflammation of IBD patients.
Identifiants
pubmed: 37600767
doi: 10.3389/fimmu.2023.1161901
pmc: PMC10436103
doi:
Substances chimiques
Chromatin
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1161901Subventions
Organisme : CIHR
ID : FDN154328
Pays : Canada
Organisme : CIHR
ID : FRN128090
Pays : Canada
Informations de copyright
Copyright © 2023 Medina, Murison, Smith, Kinker, Chakravarthy, Vitiello, Turpin, Shen, Yau, Sarmento, Faubion, Lupien, Silverberg, Arrowsmith and De Carvalho.
Déclaration de conflit d'intérêts
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.
Références
Nat Med. 2021 Nov;27(11):1970-1981
pubmed: 34675383
Front Immunol. 2019 May 28;10:1177
pubmed: 31191543
Nat Genet. 2011 Mar;43(3):246-52
pubmed: 21297633
Gastroenterology. 2004 Mar;126(3):829-39
pubmed: 14988837
Nat Methods. 2015 May;12(5):453-7
pubmed: 25822800
Nat Rev Immunol. 2014 May;14(5):329-42
pubmed: 24751956
Nat Immunol. 2007 Dec;8(12):1390-7
pubmed: 17994024
Cell. 2015 Dec 3;163(6):1400-12
pubmed: 26607794
Gut. 2002 May;50 Suppl 3:III60-4
pubmed: 11953335
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
PLoS Genet. 2012;8(3):e1002559
pubmed: 22412388
J Autoimmun. 2018 Feb;87:38-49
pubmed: 29290521
Nat Rev Immunol. 2018 Oct;18(10):617-634
pubmed: 30022149
Cell. 2019 Jul 25;178(3):714-730.e22
pubmed: 31348891
J Biol Chem. 2017 Jan 13;292(2):706-722
pubmed: 27909059
Cell. 2018 Nov 29;175(6):1701-1715.e16
pubmed: 30449622
Nat Immunol. 2012 Oct;13(10):991-9
pubmed: 22961052
Nature. 2012 Nov 1;491(7422):119-24
pubmed: 23128233
J Leukoc Biol. 2004 Jun;75(6):1010-5
pubmed: 15020649
Nat Genet. 2015 Sep;47(9):979-986
pubmed: 26192919
Nat Rev Immunol. 2008 Sep;8(9):713-25
pubmed: 19172692
Eur J Immunol. 2004 Nov;34(11):2996-3005
pubmed: 15468055
N Engl J Med. 2011 Nov 3;365(18):1713-25
pubmed: 22047562
Immunity. 2016 Nov 15;45(5):1148-1161
pubmed: 27851915
Nat Genet. 2016 Oct;48(10):1193-203
pubmed: 27526324
Gastroenterology. 2015 Oct;149(5):1163-1176.e2
pubmed: 26255561
Lancet. 2012 Nov 3;380(9853):1590-605
pubmed: 22914295
Nat Biotechnol. 2018 Jun;36(5):411-420
pubmed: 29608179
Nature. 2012 Sep 6;489(7414):75-82
pubmed: 22955617
Gastroenterology. 2020 Aug;159(2):591-608.e10
pubmed: 32428507
Nat Commun. 2021 Mar 26;12(1):1921
pubmed: 33771991
J Allergy Clin Immunol. 2018 Sep;142(3):728-743
pubmed: 30195378
Bioinformatics. 2010 Jan 1;26(1):139-40
pubmed: 19910308
Gastroenterology. 2017 Feb;152(2):313-321.e2
pubmed: 27793607
Nat Rev Immunol. 2009 Feb;9(2):91-105
pubmed: 19151746
Prim Care. 2017 Dec;44(4):673-692
pubmed: 29132528
Gastroenterology. 2006 Aug;131(2):485-96
pubmed: 16890603
Arch Pathol Lab Med. 2016 May;140(5):413-28
pubmed: 27128299
Immunity. 2019 Mar 19;50(3):629-644.e8
pubmed: 30737147
Best Pract Res Clin Rheumatol. 2017 Dec;31(6):777-796
pubmed: 30509440
Cell. 2019 Sep 5;178(6):1493-1508.e20
pubmed: 31474370
Nat Rev Gastroenterol Hepatol. 2019 May;16(5):296-311
pubmed: 30787446
Nat Genet. 2017 Feb;49(2):256-261
pubmed: 28067908
Gut. 2012 Dec;61(12):1693-700
pubmed: 22595313
Nat Rev Immunol. 2016 Jul;16(7):421-32
pubmed: 27265595
J Exp Med. 2008 Aug 4;205(8):1903-16
pubmed: 18663128
Nature. 2011 Jun 15;474(7351):307-17
pubmed: 21677747
J Crohns Colitis. 2016 Mar;10(3):338-45
pubmed: 26589954
Nat Genet. 2016 May;48(5):510-8
pubmed: 26974007
Nat Immunol. 2014 Aug;15(8):701-3
pubmed: 25045871
Nat Rev Immunol. 2003 Jul;3(7):521-33
pubmed: 12876555
Nature. 2010 Oct 21;467(7318):967-71
pubmed: 20962846
Gut. 2009 Aug;58(8):1152-67
pubmed: 19592695
Cell. 2006 Sep 22;126(6):1121-33
pubmed: 16990136
Nat Commun. 2017 Nov 17;8(1):1600
pubmed: 29150604