Abstract
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 (TRM) memory cells within two days post challenge. Further interrogation of how NK cell ablation enhances respiratory TRM indicated that TRM 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.
Highlights
Natural Killer (NK) cells are among the first effectors to directly contact influenza and influenzainfected cells and their activation affects their intrinsic functions, and subsequent CD8+ T cell responses
We examined the net contribution of NK cells to the subsequent generation of anti-influenza CD8+ Tmem subsets
We found that NK cell depletion during influenza infection results in numerically increased CD8+ Tmem (Fig. 1B) akin to what has been reported after systemic lymphocytic choriomeningitis virus (LCMV) infection[15]
Summary
Natural Killer (NK) cells are among the first effectors to directly contact influenza and influenzainfected cells and their activation affects their intrinsic functions, and subsequent CD8+ T cell responses. Further interrogation of how NK cell ablation enhances respiratory TRM indicated that TRM 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. While the signals required for the generation of T mem cells in the respiratory tract are not fully understood, CD8+ T cell fate determination is linked strength of TCR signaling, duration of T cell-APC interactions, costimulation, and CD4 help[6] Integration of these signals and cytokines in the priming environment tune PI3K and mTOR signaling pathways towards either an effector or T mem cell differentiation p rogram[6]. It is likely that NK cells could directly or indirectly influence the formation of CD8+ Tmem, making them an important variable to consider for elicitation of cross-protective C D8+ T cell immunity
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