Th1 guided evolution of protective de novo Th17 response in severe influenza

Abstract The 6.5 CD4+ T cell receptor (TCR) transgenic mice have a monotonous CD4+ TCR which responds to the hemagglutinin (HA) antigen of PR8 influenza virus. Naive 6.5 CD4+ T cells adoptively transferred into wild type mice were activated by PR8 influenza virus with Th1 response. With PR8 influenza virus infection, all CD4+ T cells in 6.5 mice were activated and they were predominantly Th1 in phenotype at the early phase of infection and Th17 at the late phase. Th1 effector responses made infected mice sick and even succumb to death. The 6.5 mice were sicker at the early phase but recovered with better survival at last. IL-17KO 6.5 mice cannot display Th17 responses and lost the survival benefit as well. IL-17 supplement at the late phase of infection enhanced survival of wild type mice with PR8 influenza virus infection. With consecutive two adoptive transfers of naive 6.5 CD4+ T cells, 6.5 CD4+ T cells of the first transfer evolved into Th1 cells but 6.5 CD4+ T cells of the second transfer demonstrated a de novoTh17 response. Thymectomy or aging in 6.5 mice limited the thymic output of naive 6.5 CD4+ T cells and diminished the Th17 response. Viral neuraminidase activated TGF-β in the Th1 6.5 CD4+ T cells at the early phase. T-bet dominance was altered with excessive ROR-γt activation in the following responding 6.5 CD4+ T cells. They have substantial IL-17 with restrained IFN-γ production. We demonstrated a Th1 guided evolution of protective Th17 response in severe influenza.