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.
Highlights
BACKGROUND & AIMSThe intestinal immune system is tightly regulated to prevent responses against the many nonpathogenic antigens in the gut
As previously shown,[6,7] we found that CD103ϩ dendritic cells (DCs) isolated from the gut-draining mesenteric lymph node (mLN) have an enhanced ability to induce Foxp3ϩ inducible regulatory T cell (iTreg) compared with CD103Ϫ DCs (Figure 1A)
Intestinal CD103ϩ DCs have emerged as key cells in maintaining gut tolerance, with recent data showing that these cells have the enhanced ability to induce guthoming receptors on responding T cells[15] and convert naïve T cells to immune-suppressive Foxp3ϩ iTregs.[6,7]
Summary
BACKGROUND & AIMSThe intestinal immune system is tightly regulated to prevent responses against the many nonpathogenic antigens in the gut. Transforming growth factor (TGF)- is a cytokine that maintains intestinal homeostasis, in part by inducing Foxp3ϩ regulatory T cells (Tregs) that suppress immune responses. We investigated the cellular and molecular pathways that control activation of TGF- and induction of Foxp3ϩ 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- and induce Foxp3ϩ Tregs in vitro. RESULTS: A tolerogenic subset of intestinal DCs that express CD103 were specialized to activate latent TGF-, and induced Foxp3ϩ Tregs independently of the vitamin A metabolite retinoic acid. The integrin ␣v8, which activates TGF-, was significantly up-regulated on CD103ϩ intestinal DCs. DCs that lack expression of integrin ␣v8 had reduced ability to activate latent TGF- and induce Foxp3ϩ Tregs in vitro and in vivo. CONCLUSIONS: CD103؉ intestinal DCs promote a tolerogenic environment in the intestines of mice via integrin ␣v8-mediated activation of TGF-
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