SIRPα is An Inhibitory Receptor That Regulates NK Cell Activation and Function

Signal regulatory protein alpha (SIRPα) is an inhibitory receptor expressed on macrophages and dendritic cells. Recent cancer research studies have reported evidence of upregulation of SIRPα on natural killer (NK) cells. The present study aimed to investigate the role of SIRPα in NK cells during viral infection.

We utilized SIRPα knockout mice (SIRPα-/-) and lymphocytic choriomeningitis virus (LCMV) infection to examine the role of SIRPα in NK cells. Flow cytometry, in vivo killing assays, and molecular analyses were performed to assess NK cell activation, cytotoxic function, and associated signaling pathways.

SIRPα expression was induced on NK cells during LCMV infection. The absence of SIRPα in knockout mice resulted in an increased proportion and activation of NK cells, with enhanced expression of cytotoxic markers and augmented NK cell-mediated killing of target cells. Mechanistically, loss of SIRPα was associated with downregulation of Src homology region 2-containing protein tyrosine phosphatase-1 (SHP-1) in NK cells. Importantly, SIRPα deficiency led to concomitant loss of CD8+ T cells and impaired viral control. In vivo killing assays indicated that activated NK cells mediated CD8+ T cell depletion in SIRPα-/- mice. Experimental NK cell depletion in these mice partially restored T cell immunity, reduced immunopathology, and improved viral clearance.

Our findings identify SIRPα as a critical inhibitory receptor that regulates NK cell effector functions. Loss of SIRPα unleashes NK cell activity but results in CD8+ T cell depletion and impaired antiviral immunity, highlighting the dual role of SIRPα in balancing NK cell activation and adaptive immune responses.