SLAMF9 regulates pDC homeostasis and function in health and disease

Abstract

SLAMF9 belongs to the conserved lymphocytic activation molecule family (SLAMF). Unlike other SLAMs, which have been extensively studied, the role of SLAMF9 in the immune system remained mostly unexplored. By generating CRISPR/Cas9 SLAMF9 knockout mice, we analyzed the role of this receptor in plasmacytoid dendritic cells (pDCs), which preferentially express the SLAMF9 transcript and protein. These cells display a unique capacity to produce type I IFN and bridge between innate and adaptive immune response. Analysis of pDCs in SLAMF9−/− mice revealed an increase of immature pDCs in the bone marrow and enhanced accumulation of pDCs in the lymph nodes. In the periphery, SLAMF9 deficiency resulted in lower levels of the transcription factor SpiB, elevation of pDC survival, and attenuated IFN-α and TNF-α production. To define the role of SLAMF9 during inflammation, pDCs lacking SLAMF9 were followed during induced experimental autoimmune encephalomyelitis. SLAMF9−/− mice demonstrated attenuated disease and delayed onset, accompanied by a prominent increase of immature pDCs in the lymph node, with a reduced costimulatory potential and enhanced infiltration of pDCs into the central nervous system. These results suggest the crucial role of SLAMF9 in pDC differentiation, homeostasis, and function in the steady state and during experimental autoimmune encephalomyelitis.

Signalling lymphocyte activation molecule family member 9 is found on select subsets of antigen‐presenting cells and promotes resistance to Salmonella infection

“…However, Sever et al also reported a relative decrease in the frequency of TNF-a-producing pDCs in CpG-stimulated lymph node cells from Slamf9 À/À mice with experimental autoimmune encephalomyelitis. 30 If optimal TNF-a production is dependent on SLAMF9 expression across multiple cell types, this may help to explain the impaired clearance of Salmonella in our studies.…”

“…The expression of SLAMF9 by pDCs was corroborated by recent literature. 30 Among CD11b + cells, weak expression of SLAMF9 is found in CD11c high conventional DCs, whereas highest expression of SLAMF9 in myeloid cells was found among a fraction of CD11c low cells corresponding to the Ly6Cmonocyte subset observed in blood (Fig. 3g).…”

SLAM Family Receptor Signaling in Viral Infections: HIV and Beyond

“…pDC stimulation through TLR7/8/9 triggers production of high levels of IFNα which orchestrates global anti-viral responses across nearly all cell types [28]. It has been shown recently that SLAMF9 signaling contributes to proper migration and function of pDCs [29], indicating a potential role for SLAMF9 in pDC-mediated antiviral responses. Following the acute phase of HIV infection, plasma viremia drops significantly, and circulating CD4 + T cell levels return to normal levels.…”

“…Regulation of macrophage and pDC responses [21,29] Monocytes, pDCs, DCs, T cells, B cells, macrophages.…”

“…Indeed, a published abstract has stated that SLAMF9 knockout mice display impaired clearance of Salmonella Typhimurium [100]. Additionally, it has been shown that SLAMF9 is highly expressed on pDCs, where it is able to regulate their function and mouse susceptibility to Experimental Autoimmune Encephalomyelitis (EAE) [29]. The ability of SLAMF9 to control pDCs function suggests that this receptor may play a role indirectly in controlling viral infections, as pDCs are known to be critical in this respect [101].…”