Licensing Delineates Helper and Effector NK Cell Subsets During Viral Infection. Mus musculus

Natural killer (NK) cells can be divided into phenotypic subsets based on the expression of receptors that bind self-MHC-I molecules with differing affinities; a concept termed licensing or education. Here we show that NK cell subsets exhibit markedly different migratory, effector, and immunoregulatory functions on dendritic cells and antigen-specific CD8+ T cell responses during influenza and murine cytomegalovirus infections. Shortly after infection, unlicensed NK cells preferentially trafficked to draining lymph nodes and produced GM-CSF, which promoted the expansion and activation of dendritic cells, and ultimately resulted in sustained antigen-specific CD8+ T cell responses. In contrast, licensed NK cells preferentially migrated to infected parenchymal tissues and produced greater levels of interferon-γ (IFN-γ). Importantly, human NK cell subsets exhibited similar phenotypic characteristics and patterns of cytokine production. Collectively, our studies demonstrate a critical demarcation between the functions of licensed and unlicensed NK cell subsets, with the former functioning as the classical effector subset in inflamed tissues and the latter as modulators of adaptive immunity helping to prime immune responses in draining lymph nodes. Overall design: Gene expression profiling of isolated pools of unlicensed (Ly49-negative, Ly49G2/A+) and licensed (Ly49C/I+) NK cells was performed in order to confirm the unique phenotypic and functional characteristics of these subsets. For this, unlicensed (CD3-CD122+Ly49G2+Ly49A+Ly49C/I- and CD3-CD122+Ly49G2 A Ly49C/I-; referred to as Ly49G2/A+ and Ly49-negative, respectively) and licensed (CD3-CD122+Ly49G2-A-Ly49C/I+; referred to as Ly49C/I+) NK cells were isolated by fluorescence-activated cell sorting of splenocytes from 30 naïve C57BL/6 mice. Total cellular RNA was isolated and then microarray gene expression profiling performed with Affymetrix GeneChip Mouse Gene 2.0 Sense Target (ST) Arrays.