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SIRP on CD11c+ cells induces Th17 cell differentiation and subsequent inflammation in the CNS in experimental autoimmune encephalomyelitis

Nishimura, T;Saito, Y;Washio, K;Komori, S;Respatika, D;Kotani, T;Murata, Y;Ohnishi, H;Mizobuchi, S;Matozaki, T;

Signal regulatory protein (SIRP) is expressed predominantly on type 2 conventional dendritic cells (cDC2s) and macrophages. We previously showed that mice systemically lacking SIRP were resistant to experimental autoimmune encephalomyelitis (EAE). Here we showed that deletion of SIRP in CD11c+ cells of mice (SirpaDC mice) also markedly ameliorated the development of EAE. The frequency of cDCs and migratory DCs (mDCs), as well as that of Th17 cells, were significantly reduced in draining lymph nodes of SirpaDC mice at the onset of EAE. In addition, we found the marked reduction in the number of Th17 cells and DCs in the CNS of SirpaDC mice at the peak of EAE. Whereas inducible systemic ablation of SIRP before the induction of EAE prevented disease development, that after EAE onset did not ameliorate the clinical signs of disease. We also found that EAE development was partially attenuated in mice with CD11c+ cell-specific ablation of CD47, a ligand of SIRP. Collectively, our results suggest that SIRP expressed on CD11c+ cells such as cDC2s and mDCs is indispensable for the development of EAE, being required for the priming of self-reactive Th17 cells in the periphery as well as for the inflammation in the CNS. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.