NK cells modify anti-influenza CD8 T cell responses and memory formation (VIR2P.1014)

Natural Killer (NK) cells are part of the first line of defense against viral infection as they quickly mobilize and eliminate infected cells independent of prior activation. However, recent evidence also suggests that NK cell activity can influence subsequent adaptive immune responses via contact dependent and independent interactions with APCs and effector T cells. Despite the importance of NK cells in coordinating these early responses, little is known regarding how this NK cell-mediated tuning regulates long-term anti-viral immunity. Using an antibody depletion method, we studied how loss of NK cells impacts the formation and maintenance of influenza-specific memory CD8 T cells. We find that in the absence of NK cells, there are increased numbers of influenza-specific CD8 T cells at the peak of the response and persisting into memory, with a skewed memory phenotype apparent earlier than observed in non-depleted mice. Loss of NK cells also reduced levels of lung-derived IFNγ and indoleamine 2,3-dioxygenase (IDO), known T cell modulators. Moreover, the anti-influenza response after heterologous challenge was also altered in the NK cell depleted cohort. Together these data suggest that NK-derived IFNγ may regulate local immunity by suppressing anti-viral memory CD8 T cell development. Importantly, loss of NK cell-derived signals has long-term consequences suggesting that differential regulation of NK cell activation should be considered in rational vaccine design.