Enhanced generation of influenza-specific tissue resident memory CD8 T cells in NK-depleted mice

Natural Killer (NK) cells are among the first effectors to directly contact influenza and influenza-infected cells and their activation affects not only their intrinsic functions, but also subsequent CD8(+) T cell responses. We utilized a NK cell depletion model to interrogate the contribution of NK cells to the development of anti-influenza CD8(+) T cell memory. NK cell ablation increased the number of influenza-specific memory CD8(+) T cells in the respiratory tract and lung-draining lymph node. Interestingly, animals depleted of NK cells during primary influenza infection were protected as well as their NK-intact counterparts despite significantly fewer reactivated CD8(+) T cells infiltrating the respiratory tract after lethal, heterosubtypic challenge. Instead, protection in NK-deficient animals seems to be conferred by rapid reactivation of an enlarged pool of lung tissue-resident (T(RM)) memory cells within two days post challenge. Further interrogation of how NK cell ablation enhances respiratory T(RM) indicated that T(RM) development is independent of global and NK cell derived IFN-γ. These data suggest that reduction in NK cell activation after vaccination with live, non-lethal influenza virus increases compartmentalized, broadly protective memory CD8(+) T cell generation and decreases the risk of CD8(+) T cell-mediated pathology following subsequent influenza infections.