Expression of αvβ8 integrin on dendritic cells regulates Th17 cell development and experimental autoimmune encephalomyelitis in mice

Abstract

Th17 cells promote a variety of autoimmune diseases, including psoriasis, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. TGF-β is required for conversion of naive T cells to Th17 cells, but the mechanisms regulating this process are unknown. Integrin αvβ8 on DCs can activate TGF-β, and this process contributes to the development of induced Tregs. Here, we have now shown that integrin αvβ8 expression on DCs plays a critical role in the differentiation of Th17 cells. Th17 cells were nearly absent in the colons of mice lacking αvβ8 expression on DCs. In addition, these mice and the DCs harvested from them had an impaired ability to convert naive T cells into Th17 cells in vivo and in vitro, respectively. Importantly, mice lacking αvβ8 on DCs showed near-complete protection from experimental autoimmune encephalomyelitis. Our results therefore suggest that the integrin αvβ8 pathway is biologically important and that αvβ8 expression on DCs could be a therapeutic target for the treatment of Th17-driven autoimmune disease.

Mouse and human lung fibroblasts regulate dendritic cell trafficking, airway inflammation, and fibrosis through integrin αvβ8–mediated activation of TGF-β

“…Expression of the other major integrin subunit involved in TGF-β activation, Itgb6, was unchanged (data not shown). We were not able to assess levels of αvβ8 protein, since a suitable antibody to detect mouse αvβ8 does not currently exist (51,52). These results demonstrate that IL-1β upregulates Itgb8 and suggest that this upregulation causes increased activation of TGF-β, which in turn induces expression of TGF-β-responsive extracellular matrix genes.…”

“…This important subset of CD4 + T cells produces IL-17(A,F), a cytokine that has been implicated in the pathogenesis of asthma, COPD, psoriasis, arthritis, diabetes, multiple sclerosis, and inflammatory bowel disease (77)(78)(79)(80)(81)(82). Two recent studies demonstrate that the loss of αvβ8 on DCs, which are crucial APCs, protects against experimental autoimmune encephalitis through inhibition of Th17 cell differentiation (51,83). In the fibroblast conditional deletion model, there is no evidence of Cre-mediated deletion of Itgb8 by purified lung DCs; instead, loss of Itgb8 on fibroblasts indirectly impairs DC function through decreased trafficking to lymph nodes.…”

Excessive vascular sprouting underlies cerebral hemorrhage in mice lacking αVβ8-TGFβ signaling in the brain

“…We and others have shown that astroglial αVβ8 binds to and activates TGFβ1 and TGFβ3 (Cambier et al, 2005;Melton et al, 2010;Yang et al, 2007). Deletion of Itgb8 in retinal Muller glia reduces paracrine TGFβ signaling in retinal endothelia, causing hyperbranching (Allinson et al, 2012;Arnold et al, 2012;Hirota et al, 2011).…”

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

“…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). From a pathogenic perspective, DC-mediated activation of latent TGF-b also contributes to Th17-cell differentiation in vivo and the development of experimental autoimmune encephalomyelitis (EAE) (Acharya et al 2010;Melton et al 2010).…”