Loss of integrin alpha sub(v) beta sub(8) 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. TGF- beta is secreted by cells as an inactive precursor that must be activated to exert biological effects, 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 sub(v) beta sub(8) on leukocytes causes severe inflammatory bowel disease and age-related autoimmunity in mice. This autoimmune phenotype is largely due to lack of alpha sub(v) beta sub(8) on dendritic cells, as mice lacking alpha sub(v) beta sub(8) principally on dendritic cells develop identical immunological abnormalities as mice lacking alpha sub(v) beta sub(8) on all leukocytes, whereas mice lacking alpha sub(v) beta sub(8) on T cells alone are phenotypically normal. We further show that dendritic cells lacking alpha sub(v) beta sub(8) fail to induce regulatory T cells (T sub(R) cells) in vitro, an effect that depends on TGF- beta activity. Furthermore, mice lacking alpha sub(v) beta sub(8) on dendritic cells have reduced proportions of T sub(R) cells in colonic tissue. These results suggest that alpha sub(v) beta sub(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 sub(v) beta sub(8) on dendritic cells to induce and/or maintain tissue T sub(R) cells.