Heterosubtypic immunity to influenza virus mediated by MHC-E-restricted memory NK cells

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Seasonal influenza epidemics are a leading cause of morbidity and mortality worldwide, and while prophylactic immunization has proven the most efficient way to prevent influenza so far, current vaccines provide limited protection against antigenically distinct influenza strains, notably those with pandemic and/or high pathogenic potential. Therefore, innovative approaches to provide longer-lasting protection than currently licensed vaccines and against a wider variety of influenza viruses is highly desirable. Mobilization of immune effector cells with potent antiviral activity against conserved influenza antigens represents one strategy to enhance cross- protection. Classically, Natural Killer (NK) cells are viewed as nonspecific effector cells of the innate immune system that play critical roles in defense against viral infections, including influenza. Unexpectedly, for over a decade, paradigms suggesting that immunological memory is exclusively mediated by T and B cells have been challenged by several independent studies clearly demonstrating that subsets of murine, non-human primate (NHP) and human NK cells are capable of adaptive immune functions, including antigen-specificity and recall responses. Our new preliminary data now show for the first time that influenza-specific NK cells mediating potent responses against conserved influenza antigens from serologically distinct strains exist in humans and provide mechanistic evidence supporting a role for HLA-E and its activating ligand NKG2C in antigen-specific NK cell responses. Collectively, these findings suggest that vaccine strategies that concomitantly enhance the breadth, magnitude and cross-reactivity of influenza-specific memory NK cell, T cell and B cell responses might significantly improve vaccine-induced cross-protective immunity. However, mechanisms underlying the establishment and maintenance of true antigen-specific NK cell memory are largely undefined and protection mediated by influenza-specific memory NK cells remain to be determined in primate species. In this study, we propose to address the overarching hypothesis that MHC-E-restricted memory NK cells can mediate heterosubtypic protection against influenza through three focused independent Aims: (i) Characterize human influenza-specific memory NK cell responses; (ii) Assess influenza-specific memory NK cell- mediated cross-protection in macaques; and (iii) Delineate MHC-E-restricted NK cell antigen specificity against influenza. We expect these innovative studies to help develop universal influenza vaccines tailored to mobilize influenza-specific memory NK cells.