Inflammatory cues enhance TGFβ activation by distinct subsets of human intestinal dendritic cells via integrin αvβ8

Regulation of intestinal T-cell responses is crucial for immune homeostasis and prevention of inflammatory bowel disease (IBD). A vital cytokine in regulating intestinal T cells is transforming growth factor-beta (TGF beta), which is secreted by cells as a latent complex that requires activation to function. However, how TGFb activation is regulated in the human intestine, and how such pathways are altered in IBD is completely unknown. Here we show that a key activator of TGFb, integrin alpha v beta 8, is highly expressed on human intestinal dendritic cells (DCs), specifically on the CD1c(+) but not the CD141(+) intestinal DC subset. Expression was significantly upregulated on intestinal DC from IBD patients, indicating that inflammatory signals may upregulate expression of this key TGF beta-activating molecule. Indeed, we found that the Toll-like receptor 4 ligand lipopolysaccharide upregulates integrin alpha v beta 8 expression and TGFb activation by human DC. We also show that DC expression of integrin alpha v beta 8 enhanced induction of FOXP3 in CD4(+) Tcells, suggesting functional importance of integrin avb8 expression by human DC. These results show that microbial signals enhance the TGF beta-activating ability of human DC via regulation of integrin avb8 expression, and that intestinal inflammation may drive this pathway in patients with IBD.