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

Abstract

Maintaining a balance between beneficial activation of immune responses and inappropriate immune attack of normal tissues requires multiple checks and balances. The cytokine TGF-β (transforming growth factor-β) is major player in one such pathway, as a negative regulator of adaptive immunity, but it has been unclear what activates TGF-β and which immune cells are critical to its action. Now the integrin αvβ8 has been identified as a critical activator of TGF-β; loss of this integrin on tissue dendritic cells activates TGF-β, which in turn induces regulatory T cells. In the absence of this pathway, mice develop autoimmunity and severe inflammation of the colon that resembles human ulcerative colitis. It is shown that mice deficient for β8 integrin develop colitis, and that β8 needs to be expressed by dendritic cells rather than T cells for colitis to develop. In addition, a decrease of T cells in the gut but not adjacent lymph nodes in diseased animals is shown. It is concluded that αVβ8-mediated integrin activation of dendritic cells is essential for prevention of colitis-inducing immune dysfunction. 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.