What Shapes Intestinal Dendritic Cells into Critical Gatekeepers of TGF-beta-Dependent T Cell Responses in the Gut

Induced regulatory T cells (iTregs) and Th17 cells are critical components of intestinal immune responses and breakdown of their balance has been associated with the development of Inflammatory Bowel Disease. Interestingly, development of both iTreg and Th17 cells requires TGF-β, which thus has a critical role in maintenance of gut immune homeostasis. Importantly TGF-β is ubiquitously expressed in an inactive latent form and must be activated before it can signal to T cells. TGF-β signaling to T cells requires activation of latent TGF-β by αvβ8 integrin on DCs. Recently, we have shown that under homeostatic conditions, β8 is highly restricted to CD103⁺ DCs from MLN, conferring on these cells their preferential ability to activate TGF-β and generate Tregs. However, the precise mechanisms by which DCs acquire this specialized ability to activate TGF-β and orchestrate T cells responses are unknown.

Here we present evidence that signals from the mucosal microenvironment promote induction of β8 expression in DCs, hence its preferential expression in DCs derived from the gut. This is dependent on both immune-, dietary- and microbiota-derived factors, and mice deficient in their downstream signaling present a modified pattern of β8 expression in DCs. Furthermore, we provide evidence that cell lineage participates in establishing the precise expression profile of β8 by modulating the ability of DC subsets to differentially respond to these signals. Together these data show that combination of lineage, environment and immune factors shape intestinal DCs into critical gatekeepers of TGF-β-dependent immune responses through regulation of β8 integrin expression.