Extrathymically generated regulatory t cells control mucosal th2 inflammation

ABSTRACT A balance between pro- and anti-inflammatory mechanisms at mucosal interfaces, which are sites of constitutive exposure to microbes and non-microbial foreign substances, allows for

efficient protection against pathogens yet prevents adverse inflammatory responses associated with allergy, asthma and intestinal inflammation1. Regulatory T (Treg) cells prevent systemic

and tissue-specific autoimmunity and inflammatory lesions at mucosal interfaces. These cells are generated in the thymus (tTreg cells) and in the periphery (induced (i)Treg cells), and their

dual origin implies a division of labour between tTreg and iTreg cells in immune homeostasis. Here we show that a highly selective blockage in differentiation of iTreg cells in mice did not

lead to unprovoked multi-organ autoimmunity, exacerbation of induced tissue-specific autoimmune pathology, or increased pro-inflammatory responses of T helper 1 (TH1) and TH17 cells.

However, mice deficient in iTreg cells spontaneously developed pronounced TH2-type pathologies at mucosal sites—in the gastrointestinal tract and lungs—with hallmarks of allergic

inflammation and asthma. Furthermore, iTreg-cell deficiency altered gut microbial communities. These results suggest that whereas Treg cells generated in the thymus appear sufficient for

control of systemic and tissue-specific autoimmunity, extrathymic differentiation of Treg cells affects commensal microbiota composition and serves a distinct, essential function in

restraint of allergic-type inflammation at mucosal interfaces. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS

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institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS SELECTIVE IL-27 PRODUCTION BY INTESTINAL REGULATORY T CELLS PERMITS GUT-SPECIFIC

REGULATION OF TH17 CELL IMMUNITY Article 06 November 2023 MUCOSAL TISSUE REGULATORY T CELLS ARE INTEGRAL IN BALANCING IMMUNITY AND TOLERANCE AT PORTALS OF ANTIGEN ENTRY Article 29 November

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ACKNOWLEDGEMENTS We thank T. Tedder for depleting CD20 antibody, R. Tudor for assistance interpreting lung pathology, P. DeRoos for assistance with Ig ELISA assays, B. Johnson for

immunohistochemical expertise, Y. Chen for assistance with airway measurements, and E. Pamer, L. Lipuma, A. Gobourne and R. Khanin for help with analysis of intestinal microbiota. This work

was supported by NIH MSTP grant GM07739 and NINDS grant 1F31NS073203-01 (R.E.N.), Strategic Young Researcher Overseas Visits Program for Accelerating Brain Circulation from Department of

Microbiology and Immunology, Keio University School of Medicine (T.C.) and NIH grant R37 AI034206 (A.Y.R.). A.Y.R is an investigator with the Howard Hughes Medical Institute. AUTHOR

INFORMATION Author notes * Steven Z. Josefowicz and Rachel E. Niec: These authors contributed equally to this work. AUTHORS AND AFFILIATIONS * Howard Hughes Medical Institute and Immunology

Program, Sloan Kettering Institute, New York, 10021, New York, USA Steven Z. Josefowicz, Rachel E. Niec, Takatoshi Chinen & Alexander Y. Rudensky * Laboratory of Chromatin Biology and

Epigenetics, The Rockefeller University, New York, 10065, New York, USA Steven Z. Josefowicz * Division of Immunology, Children’s Hospital, Harvard Medical School, Boston, 02115,

Massachusetts, USA Hye Young Kim & Dale T. Umetsu * Department of Comparative Medicine, and Histology and Imaging Core, School of Medicine, University of Washington, Seattle, 98195,

Washington, USA Piper Treuting * Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan, Takatoshi Chinen * Nomis Foundation Laboratories for

Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, 92037, California, USA Ye Zheng Authors * Steven Z. Josefowicz View author publications You can

also search for this author inPubMed Google Scholar * Rachel E. Niec View author publications You can also search for this author inPubMed Google Scholar * Hye Young Kim View author

publications You can also search for this author inPubMed Google Scholar * Piper Treuting View author publications You can also search for this author inPubMed Google Scholar * Takatoshi

Chinen View author publications You can also search for this author inPubMed Google Scholar * Ye Zheng View author publications You can also search for this author inPubMed Google Scholar *

Dale T. Umetsu View author publications You can also search for this author inPubMed Google Scholar * Alexander Y. Rudensky View author publications You can also search for this author

inPubMed Google Scholar CONTRIBUTIONS S.Z.J., R.E.N. and H.Y.K. performed experiments and analysed data, with assistance from T.C. for tissue Ig ELISA experiments, and P.T. for

immunohistochemistry and histopathology analysis. D.T.U., S.Z.J., R.E.N., H.Y.K, and A.Y.R designed and interpreted AHR experiments. Y.Z. generated CNS1- mice. S.Z.J., R.E.N. and A.Y.R.

designed experiments and wrote the paper. CORRESPONDING AUTHOR Correspondence to Alexander Y. Rudensky. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial

interests. SUPPLEMENTARY INFORMATION SUPPLEMENTARY FIGURES This file contains Supplementary Figures 1-21 with legends. (PDF 5434 kb) POWERPOINT SLIDES POWERPOINT SLIDE FOR FIG. 1 POWERPOINT

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H. _et al._ Extrathymically generated regulatory T cells control mucosal TH2 inflammation. _Nature_ 482, 395–399 (2012). https://doi.org/10.1038/nature10772 Download citation * Received: 06

July 2011 * Accepted: 06 December 2011 * Published: 08 February 2012 * Issue Date: 16 February 2012 * DOI: https://doi.org/10.1038/nature10772 SHARE THIS ARTICLE Anyone you share the

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