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

Abstract

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(v)beta8 on leukocytes causes severe inflammatory bowel disease and age-related autoimmunity in mice. This autoimmune phenotype is largely due to lack of alpha(v)beta8 on dendritic cells, as mice lacking alpha(v)beta8 principally on dendritic cells develop identical immunological abnormalities as mice lacking alpha(v)beta8 on all leukocytes, whereas mice lacking alpha(v)beta8 on T cells alone are phenotypically normal. We further show that dendritic cells lacking alpha(v)beta8 fail to induce regulatory T cells (T(R) cells) in vitro, an effect that depends on TGF-beta activity. Furthermore, mice lacking alpha(v)beta8 on dendritic cells have reduced proportions of T(R) cells in colonic tissue. These results suggest that alpha(v)beta8-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)beta8 on dendritic cells to induce and/or maintain tissue T(R) cells.

The critical contribution of TGF‐β to the induction of Foxp3 expression and regulatory T cell function

“…The T reg induced T reg express a fully functional suppressor phenotype both in vitro and in vivo. It is as yet unknown how the T reg expressed TGF-b-LAP is activated, although it does not appear to require DC or aV integrins [15].…”

“…The activated T reg would then induce Foxp3 in T cells specific for the same antigen or a different antigen presented by the same DC in a cell contact-dependent manner. This pathway would represent a carefully regulated mechanism for the expansion of antigen-specific T reg and may be critical in protecting the host from pathogeninduced autoimmune diseases such as colitis [15,16].…”

Regulation of the Immune Response by TGF-β: From Conception to Autoimmunity and Infection

“…3A). Mice with myeloid or DC-specific loss of the av integrins, which play key roles in integrin-mediated activation of TGF-b, develop colitis, showing that DCs play an important role in T-cell tolerance mediated by TGF-b (Lacy-Hulbert et al 2007;Travis et al 2007). A subset of mucosal CD103 þ DCs also specifically promote tolerance by inducing pTreg-cell differentiation (Coombes et al 2007;Sun et al 2007) likely by enabling integrin-mediated activation of TGF-b (Paidassi et al 2011;Worthington et al 2011).…”

The Foxp3+ regulatory T cell: a jack of all trades, master of regulation

“…In the intestine, it has been shown that CD103 + DCs have the unique ability to induce adaptive T reg cells because of their ability to produce retinoic acid, which is needed to induce naive T cells to differentiate into Foxp3-expressing T reg cells 47 . TGF-β induces CD103 expression 45 ; thus, TGF-β may contribute to the induction and/or maintenance of these specialized DCs. This model is consistent with the 'hygiene hypothesis', proposed to explain the reciprocal rates of infection and atopic and autoimmune disease.…”

“…Latent TGF-β binds to DCs through interaction with α V β 8 integrins on the basis of an Arg-Gly-Asp motif. This binding is essential for the provision of a substrate for TGF-β activation and prevention of colitis 45 . Evidence has been presented that furin, an enzyme purported to cleave latent TGF-β, is made by T cells after stimulation with IL-12 and thus might influence the creation of inflammatory and regulatory milieus 46 .…”