Th1-guided de novoTh17 response alleviates lung inflammation through IL-17-EGFR-TRAF4 signaling cascade in severe influenza

Abstract

Abstract Excessive inflammation is a postulated cause of severe disease and death in respiratory virus infections. In response to severe influenza virus infection, adoptively transferred naïve hemagglutinin-specific CD4 +T cells from CD4 +TCR-transgenic 6.5 mice drive an IFN-γ-producing Th1 response in wild-type mice. It helps in virus clearance but also causes collateral damage and disease aggravation. The donor 6.5 mice have all the CD4 +T cells with TCR specificity toward influenza hemagglutinin. Still, the infected 6.5 mice do not suffer from robust inflammation and grave outcome. The initial Th1 response wanes with time, and a prominent Th17 response of recent thymic emigrants alleviates inflammation and bestows protection in 6.5 mice. The severe disease in older than younger adult 6.5 mice with aging-related thymic involution and waning Th17 response further supports the protective role of the de novo Th17 response in severe influenza. Our results suggest that viral neuraminidase-activated TGF-β of the Th1 cells guides the Th17 evolution. IL-17 up-regulates and phosphorylates the non-canonical IL-17 receptor EGFR, activates the scaffold protein TRAF4, and promotes the translocation of TRAF4 to the EGFR signaling complex. Taken together, Th1-guided de novo Th17 response alleviates lung inflammation through the IL-17-EGFR-TRAF4 signaling cascade in severe influenza. The Research Center for Emerging Viral Infections receives support from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE), Taiwan and NSTC 111-2634-F-182-001 from the National Science and Technology Council, Taiwan. This work was supported by Projects MOST 111-2314-B-182-029 (AD) and MOST-105-2321-B-182A-003-MY3 (AD) from the National Science and Technology Council, Taiwan, and by CMRPG3L1671 (CTH), CMRPVVJ0052 (CTH), and CMRPG3J1771 (CYH) from the Medical Research Project Fund, Chang Gung Memorial Hospital, Taiwan.