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

Abstract

Background & AimsThe intestinal immune system is tightly regulated to prevent responses against the many nonpathogenic antigens in the gut. Transforming growth factor (TGF)-β is a cytokine that maintains intestinal homeostasis, in part by inducing Foxp3+ regulatory T cells (Tregs) that suppress immune responses. TGF-β is expressed at high levels in the gastrointestinal tract as a latent complex that must be activated. However, the pathways that control TGF-β activation in the intestine are poorly defined. We investigated the cellular and molecular pathways that control activation of TGF-β and induction of Foxp3+ Tregs in the intestines of mice to maintain immune homeostasis.MethodsSubsets of intestinal dendritic cells (DCs) were examined for their capacity to activate TGF-β and induce Foxp3+ Tregs in vitro. Mice were fed oral antigen, and induction of Foxp3+ Tregs was measured.ResultsA tolerogenic subset of intestinal DCs that express CD103 were specialized to activate latent TGF-β, and induced Foxp3+ Tregs independently of the vitamin A metabolite retinoic acid. The integrin αvβ8, which activates TGF-β, was significantly up-regulated on CD103+ intestinal DCs. DCs that lack expression of integrin αvβ8 had reduced ability to activate latent TGF-β and induce Foxp3+ Tregs in vitro and in vivo.ConclusionsCD103+ intestinal DCs promote a tolerogenic environment in the intestines of mice via integrin αvβ8-mediated activation of TGF-β.

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

“…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). 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).…”

Induction of Immune Tolerance to Dietary Antigens

“…CD103 + mLN DCs also express a higher level of latent associated binding protein 3 (LTBP3) and tissue plasminogen activator (tPA), important for secretion and activation of latent TGF-β, respectively, than CD103 − DCs in mLN (Coombes et al 2007). Furthermore, intestine-derived CD103 + DCs, but not CD103 − mLN DCs or splenic DCs, also specifically express integrin αvβ8 (Paidassi et al 2011;Worthington et al 2011), which have been shown to activate latent TGF-β. While other agents that can activate latent TGF-β exist, such as tPA, protease plasmin, thrombosponin-1, MMP2 and MMP9, αvβ8 appears essential for generation of pTregs (Annes et al 2003).…”

A máj és az immunrendszer

“…A TGF elősegíti az angiogenesist. Kiemelt szerepe van fi broticus folyamatokban [39,40,41,42]. Szövettranszplantáció után az emelkedett TGF-β-koncentráció krónikus rejectiós szindrómát jelezhet.…”