Natural killer (NK) cells are cytotoxic innate lymphocytes that play a critical role in controlling viral infections. Although CD96 has been reported as an immune checkpoint molecule in tumor immunity, the role of CD96 in NK cell activity in viral infections remains undetermined. Here, we demonstrate that CD96 functions as an activating receptor on NK cells in mouse cytomegalovirus (MCMV) infection. CD96-deficient (Cd96) mice exhibited a high MCMV burden, as compared with wild-type (WT) mice. CD96 augmented the effector function of NK cells expressing Ly49H, an activating NK receptor specific for the MCMV m157 protein, against m157-expressing target cells in vitro. Mechanistically, CD96 maintained the Ly49H-mediated phosphorylation of the protein tyrosine kinases Zap70 and or Syk. These findings suggest that CD96 enhances the anti-viral activity of Ly49H NK cells against MCMV infection.
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