Tissue-Specific Determinants of Adaptive NK Cell Responses - Spleen vs Liver NK

Natural killer (NK) cells are circulating lymphocytes that possess both innate and adaptive features, the latter including antigen-specific clonal expansion and long-lived memory responses. Unlike other adaptive lymphocytes like T and B cells, NK cells are not thought to require priming in lymphoid organs during activation. However, although NK cells respond in multiple tissue sites during cytomegalovirus (CMV) infection, here we observed that early activation and virus-specific expansion occurs predominantly in the spleen. These splenic NK cells exhibited heightened TNF-a signaling, which we identify as a novel and critical regulator of both innate and adaptive responses through engagement of distinct NF-kB signaling arms downstream of TNFR2. These findings highlight the central role of the spleen as a lymphoid organ in facilitating the innate-to-adaptive transition NK cells undergo during viral infection, and provide insight into how we can better generate innate and adaptive NK cell immunity across diverse settings. Bulk RNA-Seq data of WT Ly49H+ NK from spleen or liver on day 0 and day 1 post MCMV infection. Overall design: Ly49H+ NK cells (Ly49H+ CD49b+ TCRb- CD3- CD19- F480-) were sorted from the spleen and livers of wildtype mice that were uninfected or 24 hours p.i with MCMV.