Robust homotypic and heterosubytpic immunity against Influenza A Virus in mice lacking Th1/Tc1 transcriptional machinery

Abstract T cell responses against Influenza A Virus (IAV) are dominated by IFN-γ producing CD4 (Th1) and CD8 (Tc1) cells with little IL-17 production. However, loss of the transcription factors T-bet (Tbx21), the master Th1 regulator, and its paralog, Eomesodermin (Eomes), that influences both Th1 and Tc1 functionality, unleashes a strong Th17/Tc17 response while nearly eradicating IFN-γ production and other Th1/Tc1 hallmarks of antiviral T cells. Although Tbx21−/−Eomes−/− mice infected with LCMV were shown to succumb to Tc17 mediated wasting disease, we find that Tbx21−/−Eomes−/− mice survive primary H1N1 IAV infection and clear the virus with similar kinetics as do wild type (WT) mice. Long-lived IAV-specific IgG titers are also similar between Tbx21−/−Eomes−/− and WT mice, correlating with comparable follicular T helper cell responses. Furthermore, primed Tbx21−/−Eomes−/− mice maintain robust homotypic protection against supralethal H1N1 rechallenge indicating highly functional humoral immunity. Strikingly, H1N1-primed Tbx21−/−Eomes−/− mice also survive supralethal H3N2 IAV challenge, indicating intact heterosubtypic immunity as judged by similar viral control, weight loss kinetics and remarkably, no differences in immunopathology versus WT mice despite an overwhelming Th17/Tc17-biased inflammatory response. This cross-protection is T cell dependent as H1N1-primed Tbx21−/−Eomes−/− mice depleted of CD4 and CD8 T cells do not recover or control the H3N2 challenge virus. Our observations thus support that T-bet- and Eomes-independent effector T cells can provide robust long-term protection, potentially extending the available mechanisms for vaccines to target T cell-mediated immunity against IAV. Supported by grants from NIH (R21AI146647)