T-cell immunity against influenza virus does not require Th1 or Th17 master regulator transcription factors

Transcriptional programming needed for CD4 T cell immunity against influenza A virus (IAV) is unclear. Most antiviral CD4 T cells fit Th1 criteria, but cells unable to develop Th1 identity, through deletion of the transcription factors T-bet and Eomesodermin, remain protective. These double knockout (DKO) cells produce Th17 cytokines and express the Th17 'master regulator', Rorγt, supporting the concept that Th17 programming is needed for Th1-independent T cell immunity. Here, we directly tested requirements for Rorγt in promoting this mode of protection using T-bet/Eomesodermin/Rorγt triple knockout (TKO) mice. We show that Th17 functions are dramatically reduced in TKO cells but that they can nevertheless transfer protection against IAV to unprimed wildtype mice. Furthermore, TKO mice efficiently clear primary IAV infection, resist lethal bacterial superinfection, and generate antibody-dependent immunity against reinfection with the same virus. Finally, T cell-dependent heterosubtypic immunity is similarly effective in IAV-primed TKO, DKO, and wildtype mice. However, strikingly different T cell response patterns and inflammatory landscapes underlie these protective outcomes, highlighted in TKO mice by Th2-linked components not typically associated with efficient viral clearance. Our results reveal an unexpected degree of flexibility in T cell responses able to combat IAV, underscoring their potential to enhance vaccine strategies.