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

Abstract

Signal regulatory protein α (SIRPα) is expressed predominantly on type 2 conventional dendritic cells (cDC2s) and macrophages. We previously showed that mice systemically lacking SIRPα were resistant to experimental autoimmune encephalomyelitis (EAE). Here, we showed that deletion of SIRPα in CD11c + cells of mice (Sirpa DC 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 Sirpa DC 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 Sirpa DC mice at the peak of EAE. Whereas inducible systemic ablation of SIRPα 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 SIRPα. Collectively, our results suggest that SIRPα 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.

Specific myeloid signatures in peripheral blood differentiate active and rare clinical phenotypes of multiple sclerosis

“…Moreover, we found that the expanded myeloid cell population also expressed CD38, previously described as defining highly inflammatory macrophages and is robustly induced in human macrophages exposed to LPS ( ± IFN-γ) inflammatory stimuli ( 58 , 59 ). Finally, regarding CD172 (SIRPa/b) expression on the identified myeloid population, it has been suggested that SIRPa on DCs is important for induction of the antigen-specific Th cells producing IL-17 and finally leading to the development of EAE ( 60 , 61 ).…”

LKB1 signalling in dendritic cells controls whole-body metabolic homeostasis by limiting T helper 17 priming

“…In the context of experimental autoimmune encephalitis, IL-6 and TGFβ-induced Th17 cells were not pathogenic, whereas IL-6, IL-1β and IL-23 induced Th17 cells were pathogenic (52,53). Furthermore, development of Th17 cells in vivo is dependent on SIRPα/CD172a expression on DCs (31,54), a marker of cDC2s that efficiently prime CD4 T cells. We previously showed that LKB1-deficient splenic cDC2s produced higher levels of IL-6 (22).…”

“…To explore a direct role for LKB1-deficient DCs in promoting Th17 polarization, we sorted hepatic type 2 conventional DCs (cDC2s), the main CD4 T cell-priming subset shown to induce Th17 priming (31), from lean CD11c WT and CD11c ΔLKB1 mice that were subcutaneously injected with Flt3L-secreting B16 melanomas to expand the in vivo DC pool (Fig. 5A).…”

SIRPα - CD47 axis regulates dendritic cell-T cell interactions and TCR activation during T cell priming in spleen

“…These defects were traced to a loss in production of TNF receptor ligands lymphotoxins LTα3 and TNF-α by SIRPα + CD4 + cDCs [ 24 ]. These findings were recently attributed to a SIRPα deficiency specifically in CD11c + immune cells [ 24 – 27 ], which affect T cell priming [ 27 ]. Because of the importance of the SIRPα-CD47 axis in immune cell homeostasis within the spleen, our goal was to identify other events in antigen priming contributed by the SIRPα - CD47 adhesion pathway, beyond the reductions in immune cell numbers.…”