β8 Integrin Expression and Activation of TGF-β by Intestinal Dendritic Cells Are Determined by Both Tissue Microenvironment and Cell Lineage

Activation of TGF-beta by dendritic cells (DCs) expressing alpha v beta 8 integrin is essential for the generation of intestinal regulatory T cells (Tregs) that in turn promote tolerance to intestinal Ags. We have recently shown that alpha v beta 8 integrin is preferentially expressed by CD103 + DCs and confers their ability to activate TGF-beta and generate Tregs. However, how these DCs become specialized for this vital function is unknown. In this study, we show that beta 8 expression is controlled by a combination of factors that include DC lineage and signals derived from the tissue microenvironment and microbiota. Specifically, our data demonstrate that TGF-beta itself, along with retinoic acid and TLR signaling, drives expression of alpha v beta 8 in DCs. However, these signals only result in high levels of beta 8 expression in cells of the cDC1 lineage, CD8 alpha(+), or CD103(+)CD11b(-) DCs, and this is associated with epigenetic changes in the Itg beta 8 locus. Together, these data provide a key illustrative example of how microenvironmental factors and cell lineage drive the generation of regulatory alpha v beta 8-expressing DCs specialized for activation of TGF-beta to facilitate Treg generation.