Loss of integrin ?v?8 on dendritic cells causes autoimmunity and colitis in mice
The cytokine transforming growth factor-? (TGF-?) is an important negative regulator of adaptive immunity. TGF-? is secreted by cells as an inactive precursor that must be activated to exert biological effects, but the mechanisms that regulate TGF-? activation and function in the immune system are poorly understood. Here we show that conditional loss of the TGF-?-activating integrin ?v?8 on leukocytes causes severe inflammatory bowel disease and age-related autoimmunity in mice. This autoimmune phenotype is largely due to lack of ?v?8 on dendritic cells, as mice lacking ?v?8 principally on dendritic cells develop identical immunological abnormalities as mice lacking ?v?8 on all leukocytes, whereas mice lacking ?v?8 on T cells alone are phenotypically normal. We further show that dendritic cells lacking ?v?8 fail to induce regulatory T cells (TR cells) in vitro, an effect that depends on TGF-? activity. Furthermore, mice lacking ?v?8 on dendritic cells have reduced proportions of TR cells in colonic tissue. These results suggest that ?v?8-mediated TGF-? 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 ?v?8 on dendritic cells to induce and/or maintain tissue TR cells.
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