Abstract

Interleukin (IL)-10 producing regulatory-type 1 T cells (Tr1) play a critical role in intestinal immune homeostasis and in the prevention of inflammatory bowel disease (IBD). While Tr1 cell are enriched in the gut, the mechanism by which they are generated in vivo is unknown. TLR6, which heterodimerizes with TLR2 for signaling, is known to be immune-suppressive, leading to IL-10 responses, including Tr1 cells. Heat shock protein 70 (Hsp70) has been shown to induce IL-10 producing T cells, but the molecular mechanisms had remained elusive. Based on the recently discovered TLR2/6-mediated mechanism of Tr1 differentiation, we investigated whether Hsp70 follows the same mechanism to induce Tr1 cells. This study demonstrated that Hsp70 promotes IL-10 producing tolerogenic DCs via TLR2/6, leading to Tr1 cells. This study showed that immune modulation by Hsp70 from the intestinal epithelium is crucial in protection against experimental colitis. This study proposes Hsp70 as a protein with amazing versatility, playing vital roles for host survival as a molecular chaperone to now an immune-modulating cytokine.