The cytokine transforming growth factor-β (TGF-β) is an important negative regulator of adaptive immunity^,,. TGF-β is secreted by cells as an inactive precursor that must be activated to exert biological effects, 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 α_vβ₈ on leukocytes causes severe inflammatory bowel disease and age-related autoimmunity in mice. This autoimmune phenotype is largely due to lack of α_vβ₈ on dendritic cells, as mice lacking α_vβ₈ principally on dendritic cells develop identical immunological abnormalities as mice lacking α_vβ₈ on all leukocytes, whereas mice lacking α_vβ₈ on T cells alone are phenotypically normal. We further show that dendritic cells lacking α_vβ₈ fail to induce regulatory T cells (T_R cells) in vitro, an effect that depends on TGF-β activity. Furthermore, mice lacking α_vβ₈ on dendritic cells have reduced proportions of T_R cells in colonic tissue. These results suggest that α_vβ₈-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 α_vβ₈ on dendritic cells to induce and/or maintain tissue T_R cells.