A role for CD47 in the development of experimental colitis mediated by SIRPα+CD103- dendritic cells

Mesenteric lymph node (mLN) CD103 (alpha E integrin)(+) dendritic cells (DCs) induce regulatory T cells and gut tolerance. However, the function of intestinal CD103(-). DCs remains to be clarified. CD47 is the ligand of signal regulatory protein. (SIRP alpha) and promotes SIRP alpha(+) myeloid cell migration. We first show that mucosal CD103(-). DCs selectively express SIRP. and that their frequency was augmented in the lamina propria and mLNs of mice that developed Th17-biased colitis in response to trinitrobenzene sulfonic acid. In contrast, the percentage of SIRP alpha(+)CD103(-). DCs and Th17 responses were decreased in CD47-deficient (CD47 knockout [KO]) mice, which remained protected from colitis. We next demonstrate that transferring wild-type (WT), but not CD47 KO, SIRP alpha(+)CD103(-). DCs in CD47 KO mice elicited severe Th17-associated wasting disease. CD47 expression was required on the SIRP alpha(+) CD103. DCs for efficient trafficking to mLNs in vivo, whereas it was dispensable on both DCs and T cells for Th17 polarization in vitro. Finally, administration of a CD47-Fc molecule resulted in reduced SIRP alpha(+)CD103(-). DC-mediated Th17 responses and the protection of WT mice from colitis. We thus propose SIRP alpha(+)CD103(-). DCs as a pathogenic DC subset that drives Th17-biased responses and colitis, and the CD47-SIRP alpha axis as a potential therapeutic target for inflammatory bowel disease.