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.