Neuraminidase-mediated TGF-β activation facilitates evolution of protective Th17 immunity

Abstract

Abstract The immune system responds to influenza virus infection for eradication of the virus but the associated inflammation may cause tissue damage to the host. In our antigen-specific mouse system, naïve influenza hemagglutinin (HA)-specific CD4+ T cells adoptively transferred with infection respond with Th1 phenotype and produce IFN-γ. Some of them secrete IL-17 as well. Second batch HA specific CD4+ T cells, adoptively transferred on day 4 after infection and the first transfer, respond to the infection with Th17 phenotype. They produce IL-17 but not IFN-γ. Both the Th1 and Th17 cells are activated with similar levels of ZAP-70 phosphorylation and T-bet induction. For the Th17 cells, IFN-γ deficiency is associated with excessive ROR-γt induction and altered T-bet dominance. Th17 cells display surface LAG-3 expression, suppress T cell activation in vitro and decrease lung inflammation in vivo. The evolution of Th17 cells is augmented in IL-10 deficiency, with IL-10 knockout mice as the recipients transferred with IL-10 knockout HA specific CD4+ T cells. There is increased neuraminidase-mediated TGF-β activation in this IL-10 deficient environment. Viral neuraminidase mediated TGF-β activation in the first batch of HA specific CD4+ T cells facilitates the Th17 evolution of the 2nd batch of cells. The 6.5 T cell receptor (TCR) transgenic mice of monotonous HA specific TCR repertoire respond to influenza virus infection with Th17 deviation and demonstrate survival benefit. Consecutive waves of naïve HA specific T cells from the thymus in 6.5 mice may evolve with mechanisms similar to consecutive adoptive transfers. Evolution of protective Th17 immunity is facilitated by neuraminidase-mediated TGF-β activation.