Highly protective T-h17-polarized responses against Influenza A Virus develop in the absence of CD4 T cell-intrinsic T-bet and Eomes expression

Abstract

Abstract Though bulk CD4 T cell responses against influenza A virus (IAV) are characterized as Th1, expression of the transcription factor T-bet (Tbx21), the ‘master regulator’ of Th1 fate, is not required for mice to clear IAV. While the Tbx21−/− CD4 T cells develop some Th17 characteristics in the infected lung, they still retain relatively high Th1 functionality including robust IFNγ production. Here, we show that the transcription factor Eomesodermin (Eomes) is required for the residual Th1 identity of Tbx21−/− cells by comparing Tbx21−/− and double Tbx21−/−Eomes− /− CD4 T cells in an adoptive transfer model of IAV infection. The Tbx21−/−Eomes−/− cells not only lose Th1 attributes but develop much stronger Th17 attributes versus Tbx21−/− cells. The elaboration of Th17 responses by Tbx21−/− Eomes−/− cells is not a default effector state but requires receipt of both IL-6 and TGFβ in IAV-infected lungs. Similar Th17 identity in the absence of Th1 attributes are seen analyzing CD4 T cells in Tbx21−/−Eomes−/− mice infected with IAV, and this response correlates with protection as CD4 T cell depletion abrogates viral control. To more stringently test the protective capacity of Th17 responses, we transferred in-vitro Th17 primed WT or Tbx21−/−Eomes−/− effectors to unprimed WT hosts and challenged with lethal IAV. Both populations protected, but while WT Th17 cells gained Th1 characteristics in vivo, Tbx21−/−Eomes−/− cells strengthened their Th17 functionality remarkably without any shift towards Th1 identity. Our observations thus show that prototypical Th17 cells, that cannot gain Th1 attributes through mechanisms of plasticity often seen during pathogen responses, can mediate strong protection against IAV infection.