Signal regulatory protein alpha (SIRPα) regulates the homeostasis of CD103+CD11b+DCs in the intestinal lamina propria

Charlotte L Scott,Tamsin F P Zangerle Murray,Allan Mci Mowat,Gillian Douce,Katherine S H Beckham

doi:10.1002/eji.201444859

Charlotte L Scott, Tamsin F P Zangerle Murray + Show 3 more

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https://doi.org/10.1002/eji.201444859

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Abstract

Signal regulatory protein alpha (SIRPα/CD172a) is a conserved transmembrane protein thought to play an inhibitory role in immune function by binding the ubiquitous ligand CD47. SIRPα expression has been used to identify dendritic cell subsets across species and here we examined its expression and function on intestinal DCs in mice. Normal mucosa contains four subsets of DCs based on their expression of CD103 and CD11b and three of these express SIRPα. However, loss of SIRPα signaling in mice leads to a selective reduction in the CD103+CD11b+ subset of DCs in the small intestine, colon, and among migratory DCs in the mesenteric lymph node. In parallel, these mice have reduced numbers of TH17 cells in steady-state intestinal mucosa, and a defective TH17 response to Citrobacter infection. Identical results were obtained in CD47KO mice. DC precursors from SIRPα mutant mice had an enhanced ability to generate CD103+CD11b+ DCs in vivo, but CD103+CD11b+ DCs from mutant mice were more prone to die by apoptosis. These data show a previously unappreciated and crucial role for SIRPα in the homeostasis of CD103+CD11b+ DCs in the intestine, as well as providing further evidence that this subset of DCs is critical for the development of mucosal TH17 responses.

Highlights

The intestinal immune system is exposed to a wide variety of foreign antigens including dietary constituents, commensal microorganisms and pathogens
We show that signal regulatory protein α (SIRPα) is expressed by macrophages and three distinct populations of DCs in the gut; the loss of CD47 or SIRPα signaling leads to a selective decrease in CD103+CD11b+ DCs, together with a decrease in the generation of intestinal TH17 cells
As CD103+CD11b+ DCs have recently been implicated in the homeostasis of mucosal TH17 cells [5, 6, 13, 26,27,28,29], we examined the CD4+ T-cell compartment in the small intestinal lamina propria (LP) of steady-state SIRPα mt and CD47KO animals

Summary

Introduction

The intestinal immune system is exposed to a wide variety of foreign antigens including dietary constituents, commensal microorganisms and pathogens. Signal regulatory protein alpha (SIRPα/CD172a) expression is found on the majority of myeloid cells. It is expressed differentially by subsets of DCs, being present on CD11b+ DCs in mice, but not on the DCs with cross-presenting activity. The ligand for SIRPα is the ubiquitously expressed CD47 and this interaction is generally believed to have inhibitory effects on immune function, having been implicated in the pathogenesis of a number of models of autoimmunity including experimental autoimmune encephalomyelitis, contact hypersensitivity, and collagen-induced arthritis [13,14,15,16]

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