STAT1 expression controls CD4 T cell Th1 and Th17 effector functionality during influenza virus infection

Abstract

Abstract Most CD4 T cells primed by influenza A virus (IAV) express the transcription factor T-bet, the Th1 ‘master regulator’, and are marked by phenotypic and functional Th1 hallmarks. The extent to which STAT1 and STAT4 activation, both needed for maximal T-bet induction in vitro, are required to direct IAV-primed CD4 T cell responses is not clear. Here, we transferred STAT-deficient (STAT −/−) or wildtype CD4 T cells recognizing IAV to congenic wildtype mice, challenged them with IAV, and analyzed the donor cells in the infected lungs 7 days later. STAT1 −/−cells were barely detected in host mice but were rescued when NK cells were depleted in host mice prior to infection. Functional analysis revealed compromised Th1 identity in STAT1 −/−effectors mirroring that of T-bet −/−cells. However, while T-bet −/−cells develop Th17 functions, STAT1 −/−cells do not. We show that this is due to alternative receipt of type I IFN signals by the STAT1 −/−cells, as blocking type I IFN receptor in IAV-primed mice promotes robust Th17 identity in STAT1 −/−but not in WT cells. In contrast, STAT4 −/−donor cells closely resemble WT cells. To ask if IAV-primed CD4 T cells can respond to STAT4-activating signals we treated mice receiving STAT4 −/−donor cells with IL-12 during IAV infection. IL-12 dramatically increased T-bet and Th1 cytokine production of wildtype, but not of STAT4 −/−or T-bet −/−cells. Our findings thus indicate that STAT1 activation is sufficient to direct prototypical antiviral effector identity, but that this response is not fully Th1-polarized without therapeutic STAT4 activation. This work impacts vaccine strategies that aim to promote protective T cell immunity against IAV by shaping the priming environment with STAT-activating cytokine signals.