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Loss of integrin αvβ8 on dendritic cells causes autoimmunity and colitis in mice

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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Figure 1: (Vav1-cre)Itgb8 fl/fl mice develop age-related autoimmunity.
Figure 2: (Vav1-cre)Itgb8 fl/fl mice develop enhanced numbers of activated/memory T cells expressing IL-4 and IFN-γ, and increased serum IgE, IgG1 and IgA levels.
Figure 3: Mice lacking integrin β 8 on dendritic cells develop an identical immune phenotype to mice lacking β 8 integrin on all leukocytes.
Figure 4: β 8 -deficient dendritic cells fail to induce T R cells in vitro , and (CD11c-cre)Itgb8 fl/fl mice have reduced proportions of T R cells in colonic tissue.

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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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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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