Loss of integrin αvβ8 on dendritic cells causes autoimmunity and colitis in mice (original) (raw)

Nature volume 449, pages 361–365 (2007)Cite this article

Abstract

The cytokine transforming growth factor-β (TGF-β) is an important negative regulator of adaptive immunity1,2,3. TGF-β is secreted by cells as an inactive precursor that must be activated to exert biological effects4, but the mechanisms that regulate TGF-β activation and function in the immune system are poorly understood. Here we show that conditional loss of the TGF-β-activating integrin αvβ8 on leukocytes causes severe inflammatory bowel disease and age-related autoimmunity in mice. This autoimmune phenotype is largely due to lack of αvβ8 on dendritic cells, as mice lacking αvβ8 principally on dendritic cells develop identical immunological abnormalities as mice lacking αvβ8 on all leukocytes, whereas mice lacking αvβ8 on T cells alone are phenotypically normal. We further show that dendritic cells lacking αvβ8 fail to induce regulatory T cells (TR cells) in vitro, an effect that depends on TGF-β activity. Furthermore, mice lacking αvβ8 on dendritic cells have reduced proportions of TR cells in colonic tissue. These results suggest that αvβ8-mediated TGF-β activation by dendritic cells is essential for preventing immune dysfunction that results in inflammatory bowel disease and autoimmunity, effects that are due, at least in part, to the ability of αvβ8 on dendritic cells to induce and/or maintain tissue TR cells.

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Acknowledgements

We thank D. Kioussis for providing the Vav1-Cre mice and A. Rudensky for providing the GFP–Foxp3 mice. This work was supported by grants from the National Heart, Lung and Blood Institute (to D.S.), the National Institute of Allergy and Infectious Diseases (to J.A.B and B.R.) and funds from the Sandler Program for Asthma Research (to B.R.). M.A.T. was the recipient of an American Lung Association Research Fellowship.

Author Contributions M.A.T. performed all of the experiments described and wrote most of the manuscript; B.R. generated the CD11c-Cre mice and contributed to the design and interpretation of studies using those mice; A.C.M. contributed to the studies of colonic inflammation, colonic TR cells and designed and performed all of the qPCR studies described; E.M. helped design, perform and interpret the in vitro TR cell induction assays; Q.T. helped to design, perform and interpret the studies analysing the nature of the immunological defects described; J.M.P. generated the conditional Itgb8 knockout mice and helped in the design and interpretation of genotyping assays and crosses to Cre-expressing lines; Y.W., X.B. and X.H. helped in the design, performance and interpretation of all of the studies of tissue morphology; L.F.R. oversaw the generation of the conditional Itgb8 knockout mice and contributed to the design and interpretation of studies using these animals; J.A.B. contributed to the design and interpretation of the studies characterizing the immunological abnormalities seen and analysing the contribution of TR cells; D.S. oversaw the design and interpretation of all studies described and oversaw writing of the manuscript.

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  1. Mark A. Travis
    Present address: Present address: Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, A3051 Smith Building, Oxford Road, Manchester M13 9PT, UK.,

Authors and Affiliations

  1. Department of Medicine, Lung Biology Center, University of California San Francisco, 1550 4th Street, Room 545, San Francisco, California 94158, USA,
    Mark A. Travis, Andrew C. Melton, Yanli Wang, Xin Bernstein, Xiaozhu Huang & Dean Sheppard
  2. Department of Microbiology, Columbia University, 701 West 168th Street, Room 609, New York, New York 10032, USA,
    Boris Reizis
  3. Department of Medicine, Diabetes Center, 513 Parnassus Avenue, University of San Francisco, San Francisco, California 94143, USA,
    Emma Masteller, Qizhi Tang & Jeffrey A. Bluestone
  4. Department of Physiology, Howard Hughes Medical Institute, University of California, San Francisco, California 94158, USA,
    John M. Proctor & Louis F. Reichardt

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  1. Mark A. Travis
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Correspondence toDean Sheppard.

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Travis, M., Reizis, B., Melton, A. et al. Loss of integrin αvβ8 on dendritic cells causes autoimmunity and colitis in mice.Nature 449, 361–365 (2007). https://doi.org/10.1038/nature06110

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Editorial Summary

Balancing the immune forces

Maintaining a balance between beneficial activation of immune responses and inappropriate immune attack of normal tissues requires multiple checks and balances. The cytokine TGF-β (transforming growth factor-β) is major player in one such pathway, as a negative regulator of adaptive immunity, but it has been unclear what activates TGF-β and which immune cells are critical to its action. Now the integrin αvβ8 has been identified as a critical activator of TGF-β; loss of this integrin on tissue dendritic cells activates TGF-β, which in turn induces regulatory T cells. In the absence of this pathway, mice develop autoimmunity and severe inflammation of the colon that resembles human ulcerative colitis.