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PMID: 25908663 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Immune tolerance. Group 3 innate lymphoid cells mediate intestinal selection of commensal bacteria-specific CD4⁺ T cells.

Science (New York, N.Y.) ·Vol. 348 ·No. 6238 ·2015-05-29 ·Pages 1031-5

Hepworth MR, Fung TC, Masur SH, Kelsen JR, McConnell FM, Dubrot J, Withers DR, Hugues S, Farrar MA, Reith W, Eberl G, Baldassano RN, Laufer TM, Elson CO, Sonnenberg GF

Abstract

Inflammatory CD4(+) T cell responses to self or commensal bacteria underlie the pathogenesis of autoimmunity and inflammatory bowel disease (IBD), respectively. Although selection of self-specific T cells in the thymus limits responses to mammalian tissue antigens, the mechanisms that control selection of commensal bacteria-specific T cells remain poorly understood. Here, we demonstrate that group 3 innate lymphoid cell (ILC3)-intrinsic expression of major histocompatibility complex class II (MHCII) is regulated similarly to thymic epithelial cells and that MHCII(+) ILC3s directly induce cell death of activated commensal bacteria-specific T cells. Further, MHCII on colonic ILC3s was reduced in pediatric IBD patients. Collectively, these results define a selection pathway for commensal bacteria-specific CD4(+) T cells in the intestine and suggest that this process is dysregulated in human IBD.

MeSH Terms
Animals Apoptosis/immunology Autoimmunity Bacteria/immunology CD4-Positive T-Lymphocytes/immunology Colon/microbiology Female Flagellin/genetics,immunology Histocompatibility Antigens Class II/immunology Humans Immunity, Innate Inflammatory Bowel Diseases/immunology,microbiology Lymphocyte Activation Male Mice Mice, Inbred C57BL Symbiosis Thymus Gland/immunology
Chemicals
CBir1 flagellin Histocompatibility Antigens Class II Flagellin
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Hepworth Matthew R
Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford I. Weill Department of Medicine, Gastroenterology Division, and Department of Microbiology and Immunology, Weill Cornell Medical College, Cornell University, New York, NY, USA.
Fung Thomas C
Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford I. Weill Department of Medicine, Gastroenterology Division, and Department of Microbiology and Immunology, Weill Cornell Medical College, Cornell University, New York, NY, USA. Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Masur Samuel H
Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Kelsen Judith R
Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
McConnell Fiona M
Medical Research Council, Centre for Immune Regulation, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
Dubrot Juan
Department of Pathology and Immunology, University of Geneva Medical School, Geneva, Switzerland.
Withers David R
Medical Research Council, Centre for Immune Regulation, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
Hugues Stephanie
Department of Pathology and Immunology, University of Geneva Medical School, Geneva, Switzerland.
Farrar Michael A
Center for Immunology, Department of Laboratory Medicine and Pathology, University of Minnesota, MN, USA.
Reith Walter
Department of Pathology and Immunology, University of Geneva Medical School, Geneva, Switzerland.
Eberl Gérard
Institut Pasteur, Microenvironment and Immunity Unit, Paris, France.
Baldassano Robert N
Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Laufer Terri M
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Philadelphia Veterans Affairs Medical Center, Philadelphia, PA, USA.
Elson Charles O
Departments of Medicine and Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA.
Sonnenberg Gregory F
Jill Roberts Institute for Research in Inflammatory Bowel Disease, Joan and Sanford I. Weill Department of Medicine, Gastroenterology Division, and Department of Microbiology and Immunology, Weill Cornell Medical College, Cornell University, New York, NY, USA. gfsonnenberg@med.cornell.edu.
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Article Info
Journal
Science (New York, N.Y.)
Abbr.
Science
ISSN
1095-9203
DOI
10.1126/science.aaa4812
Email
gfsonnenberg@med.cornell.edu
Published
2015-05-29
Epub
2015-00-23
Pages
1031-5
Language
English
Region
United States
NLM ID
0404511
PMCID
PMC4449822
Subset
IM
Grants
NIDDK NIH HHS · DK071176 · United States
NIH HHS · DP5OD012116 · United States
NIH HHS · DP5 OD012116 · United States
NIDDK NIH HHS · P01 DK071176 · United States
NCRR NIH HHS · UL1-RR024134 · United States
Wellcome Trust · United Kingdom
NCRR NIH HHS · UL1 RR024134 · United States
Corrections
CommentIn
PMID: 26113259
CommentIn
PMID: 26200009
External Links
PubMed source DOI: 10.1126/science.aaa4812 PMC Full Text View journal details
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