An IL-17-EGFR-TRAF4 axis contributes to the alleviation of lung inflammation in severe influenza

Adaptive transfer experiments using an influenza hemagglutinin antigen-specific mouse model suggest that viral neuraminidase-activated TGF-beta from Th1 cells guides Th17 evolution to promote protection from lung inflammation in severe influenza. Excessive inflammation is a postulated cause of severe disease and death in respiratory virus infections. In response to severe influenza virus infection, adoptively transferred naive hemagglutinin-specific CD4(+) T cells from CD4(+) TCR-transgenic 6.5 mice drive an IFN-gamma-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. Our results suggest that viral neuraminidase-activated TGF-beta of the Th1 cells guides the Th17 evolution, and IL-17 signaling through the non-canonical IL-17 receptor EGFR activates the scaffold protein TRAF4 more than TRAF6 during alleviation of lung inflammation in severe influenza.

Automated summary

Adaptive transfer experiments using an influenza hemagglutinin antigen-specific mouse model suggest that viral neuraminidase-activated TGF-beta from Th1 cells guides Th17 evolution to promote protection from lung inflammation in severe influenza.