1. Immunology and Inflammation
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CRIg, a tissue-resident macrophage specific immune checkpoint molecule, promotes immunological tolerance in NOD mice, via a dual role in effector and regulatory T cells

  1. Xiaomei Yuan
  2. Bi-Huei Yang
  3. Yi Dong
  4. Asami Yamamura
  5. Wenxian Fu  Is a corresponding author
  1. University of California, San Diego, United States
Research Article
  • Cited 14
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Cite this article as: eLife 2017;6:e29540 doi: 10.7554/eLife.29540

Abstract

How tissue-resident macrophages (TRM) impact adaptive immune responses remains poorly understood. We report a novel mechanism by which TRMs regulate T cell activities at tissue sites. This mechanism was mediated by the complement receptor of immunoglobulin family (CRIg). Using animal models for autoimmune type 1 diabetes (T1D), we found that CRIg+ TRMs form a protective barrier surrounding pancreatic islets. Genetic ablation of CRIg exacerbated islet inflammation and local T cell activation. CRIg exhibited a dual function of attenuating early T cell activation and promoting the differentiation of Foxp3+ regulatory (Treg) cells. More importantly, CRIg stabilized the expression of Foxp3 in Treg cells, by enhancing their responsiveness to interleukin-2. The expression of CRIg in TRMs was postnatally regulated by gut microbial signals and metabolites. Thus, environmental cues instruct TRMs to express CRIg, which functions as an immune checkpoint molecule to regulate adaptive immunity and promote immune tolerance.

Article and author information

Author details

  1. Xiaomei Yuan

    Pediatric Diabetes Research Center, Department of Pediatrics, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Bi-Huei Yang

    Pediatric Diabetes Research Center, Department of Pediatrics, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Yi Dong

    Pediatric Diabetes Research Center, Department of Pediatrics, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Asami Yamamura

    Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Wenxian Fu

    Pediatric Diabetes Research Center, Department of Pediatrics, University of California, San Diego, La Jolla, United States
    For correspondence
    w3fu@ucsd.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0684-8929

Funding

American Association of Immunologists

  • Xiaomei Yuan

JDRF (2-SRA-2016-306-S-B)

  • Wenxian Fu

National Institute of Diabetes and Digestive and Kidney Diseases (P30 DK063491)

  • Wenxian Fu

University of California, San Diego (UL1 TR000100)

  • Wenxian Fu

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All mice were housed under specific pathogen free (SPF) conditions in our animal facility at University of California, San Diego, in accordance with the ethical guidelines of the Institutional Animal Care and Use Committee (#S13253).

Reviewing Editor

  1. Shimon Sakaguchi, Osaka University, Japan

Publication history

  1. Received: June 12, 2017
  2. Accepted: November 22, 2017
  3. Accepted Manuscript published: November 24, 2017 (version 1)
  4. Version of Record published: December 13, 2017 (version 2)

Copyright

© 2017, Yuan et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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