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

The cytokine transforming growth factor-beta (TGF-beta) is an important negative regulator of adaptive immunity(1-3). TGF-beta is secreted by cells as an inactive precursor that must be activated to exert biological effects(4), but the mechanisms that regulate TGF-beta activation and function in the immune system are poorly understood. Here we show that conditional loss of the TGF-beta-activating integrin alpha(v)beta(8) on leukocytes causes severe inflammatory bowel disease and age-related autoimmunity in mice. This autoimmune phenotype is largely due to lack of alpha(v)beta(8) on dendritic cells, as mice lacking alpha(v)beta(8) principally on dendritic cells develop identical immunological abnormalities as mice lacking alpha(v)beta(8) on all leukocytes, whereas mice lacking alpha(v)beta(8) on T cells alone are phenotypically normal. We further show that dendritic cells lacking alpha(v)beta(8) fail to induce regulatory T cells (T-R cells) in vitro, an effect that depends on TGF-beta activity. Furthermore, mice lacking alpha(v)beta(8) on dendritic cells have reduced proportions of T-R cells in colonic tissue. These results suggest that alpha(v)beta(8)-mediated TGF-beta 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 alpha(v)beta(8) on dendritic cells to induce and/or maintain tissue T-R cells.