STAT1 protects CD4 T cells from deletion by NK cells during influenza infection and promotes Th1 identity that can be enhanced through STAT4 to improve their anti-viral impact

Abstract

Abstract Most CD4 T cells responding to influenza A virus (IAV) fit prototypical Th1 criteria including high expression of the transcription factor T-bet, the Th1 ‘master regulator’, and strong IFNg production. Optimal Th1 development in vitro also requires cytokine-dependent activation of the transcription factors STAT4 and STAT1, but how these pathways impact anti-viral responses is not clear. Here, to focus on the roles of CD4 T cell-intrinsic STAT4 and STAT1, we transferred STAT-deficient (STAT−/−) or wildtype CD4 T cells recognizing virus to congenic wildtype hosts, challenged with IAV, and analyzed donor effector responses in the infected lungs. STAT4−/− and wildtype cells reached similar numbers with no differences seen in their Th1 identity. In contrast, STAT1−/− donor cells were barely detected in host mice but reached similar numbers to wildtype donors when NK cells were depleted. Analysis of STAT1−/− cells in NK cell-depleted hosts revealed severely compromised Th1 identity that mirrored T-bet−/− donor cell responses. While these findings suggest that full Th1-polarization during IAV infection does not require STAT4, treatment of mice with IL-12 dramatically increases Th1 attributes in wildtype but not STAT4−/−CD4 T cells. This indicates that the wildtype IAV-primed CD4 T cell response is not strongly Th1-polarized. Finally, priming CD4 T cells in vitro with STAT4- and STAT1-activating cytokines promotes effector cells better able to combat IAV when transferred to unprimed mice than when only STAT1 activating signals are present. Enhancing Th1 identity through harnessing CD4 T cell-intrinsic STAT4 activation can thus improve their anti-viral impact during infection, with important implications for vaccine design.