Divergent Role for STAT5 in the Adaptive Responses of Natural Killer Cells

Natural killer (NK) cells are innate lymphocytes with the capacity to elicit adaptive features, including clonal expansion and immunological memory. Because signal transducer and activator of transcription 5 (STAT5) is essential for NK cell development, the roles of this transcription factor and its upstream cytokines interleukin-2 (IL-2) and IL-15 during infection have not been carefully investigated. In this study, we investigate how STAT5 regulates transcription during viral infection. We demonstrate that STAT5 is induced in NK cells by IL-12 and STAT4 early after infection and that partial STAT5 deficiency results in a defective capacity of NK cells to generate long-lived memory cells. Furthermore, we find a functional dichotomy of IL-2 and IL-15 signaling outputs during viral infection, whereby both cytokines drive clonal expansion, but only IL-15 is required for memory NK cell survival. We thus highlight a role for STAT5 signaling in promoting an optimal anti-viral NK cell response. [Display omitted] •STAT5 is induced in NK cells by IL-12 via STAT4 during MCMV infection•NK cells require STAT5 for protection against viral infection•IL-2 and IL-15 non-redundantly drive clonal proliferation of anti-viral NK cells•IL-15 and STAT5 promote NK cell survival during the memory phase Wiedemann et al. demonstrate that Stat5a and Stat5b are induced by IL-12 and STAT4 signaling in NK cells following MCMV infection. They further provide evidence that the cytokines IL-2 and IL-15 upstream of STAT5 differentially promote the early and late stages of the adaptive NK cell response to MCMV infection.