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A role for CD47 in the development of experimental colitis mediated by SIRP⁺CD103^– dendritic cells

¹ Research Institute of the McGill University Health Centre, McGill University, Montreal H3H 2R9, Canada
² Immunoregulation Laboratory, Research Centre of the University of Montreal Hospital Centre, Notre-Dame Hospital, Montreal H2L 4M1, Canada

CORRESPONDENCE Marika Sarfati: m.sarfati{at}umontreal.ca

Mesenteric lymph node (mLN) CD103 (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) and promotes SIRP⁺ 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⁺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⁺CD103^– DCs in CD47 KO mice elicited severe Th17-associated wasting disease. CD47 expression was required on the SIRP⁺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⁺CD103^– DC–mediated Th17 responses and the protection of WT mice from colitis. We thus propose SIRP⁺CD103^– DCs as a pathogenic DC subset that drives Th17-biased responses and colitis, and the CD47–SIRP axis as a potential therapeutic target for inflammatory bowel disease.

Abbreviations used: BMDC, bone marrow–derived DC; CD, Crohn's disease; LP, lamina propria; mLN, mesenteric lymph node; SIRP, signal regulatory protein ; TLR, Toll-like receptor; TNBS, trinitrobenzene sulfonic acid.

© 2009 Fortin et al.
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