NK cells require both inhibitory and activation Ly49 receptors to mediate MHC I Dk-dependent MCMV resistance.

Abstract

Abstract The MHC class I molecule, Dk, is a key genetic factor of murine cytomegalovirus (MCMV) resistance. NK cells expressing the C57L-derived inhibitory receptor Ly49G2 (G2) mediate Dk-dependent MCMV control, however, a precise in vivo role for activation receptors has not been delineated. We studied a role for activation receptors in Dk-disparate B6.NKCc57l congenic mice by injecting neutralizing mAbs prior to infection. We found that only Ly49R (R) blockade specifically, and completely, abrogated host resistance. R+ NK cells had a differentiated phenotype (CD27−, CD11b+, KLRG1+, DNAM1−) and displayed higher granzyme B during MCMV infection, in comparison to R− NK cells. R+ G2+ NK cells responding to MCMV also showed higher proliferative potential and cytokine responsiveness compared to R+ G2− NK cells. To further interrogate the role of these NK cell subsets in vivo, we exploited differences in expression of Nkrp1 (NK1.1) and Ly49 receptor alleles in our NKC congenic mouse strains. Endogenous NK cells in H-2 matched host B6.Dk mice were either selectively depleted with mAb PK136 (NK1.1) or neutralized with mAb 3D10 (a-Ly49H), rendering them susceptible to MCMV infection, prior to adoptive transfer of donor B6.NKCc57l NK cells. We found that responding donor NK cells were mostly R+ G2+ and actively expanding in contrast to R+ G2− NK cells. Ongoing adoptive transfer experiments with sorted NK cell populations suggest MCMV control coincides with donor R+ G2+ NK cells. We are continuing to investigate how inhibitory Ly49 receptors modify NK cell responsiveness via activation Ly49 receptors. We infer from these data that inhibitory and activation Ly49 receptors work in tandem to deliver specific NK cell-dependent virus control.