Intestinal Dendritic Cells Specialize to Activate Transforming Growth Factor-β and Induce Foxp3+ Regulatory T Cells via Integrin αvβ8

BACKGROUND & AIMS: The intestinal immune system is tightly regulated to prevent responses against the many nonpathogenic antigens in the gut. Transforming growth factor (TGF)-beta is a cytokine that maintains intestinal homeostasis, in part by inducing Foxp3(+) regulatory T cells (Tregs) that suppress immune responses. TGF-beta is expressed at high levels in the gastrointestinal tract as a latent complex that must be activated. However, the pathways that control TGF-beta activation in the intestine are poorly defined. We investigated the cellular and molecular pathways that control activation of TGF-beta and induction of Foxp3(+) Tregs in the intestines of mice to maintain immune homeostasis. METHODS: Subsets of intestinal dendritic cells (DCs) were examined for their capacity to activate TGF-beta and induce Foxp3(+) Tregs in vitro. Mice were fed oral antigen, and induction of Foxp3(+) Tregs was measured. RESULTS: A tolerogenic subset of intestinal DCs that express CD103 were specialized to activate latent TGF-beta, and induced Foxp3(+) Tregs independently of the vitamin A metabolite retinoic acid. The integrin alpha v beta 8, which activates TGF-beta, was significantly up-regulated on CD103(+) intestinal DCs. DCs that lack expression of integrin alpha v beta 8 had reduced ability to activate latent TGF-beta and induce Foxp3(+) Tregs in vitro and in vivo. CONCLUSIONS: CD103(+) intestinal DCs promote a tolerogenic environment in the intestines of mice via integrin alpha v beta 8-mediated activation of TGF-beta.