Interleukin-17A signaling promotes CD8+ T cell cytotoxicity against West Nile virus infection through enhancing PI3K-mTOR-mediated metabolism

West Nile Virus (WNV), a mosquito-borne neurotropic flavivirus, is a major
cause of viral encephalitis in the United States, posing a continuous
threat to public health. Unfortunately, no vaccine or specific therapeutic
intervention is available against WNV infection. Previous studies,
including ours, demonstrated that interleukin-17A (IL-17A) signaling
promotes the cytotoxicity of CD8+ T cells to facilitate WNV and parasite
clearance; however, the molecular mechanism is not understood. IL-17
receptor C (IL-17RC) is an obligatory co-receptor with IL-17 receptor A
(IL-17RA) for signaling induced by IL-17A, IL-17A/F, and IL-17F. In this
study, we found that IL-17RC deficient (Il17rc-/-) mice were more
susceptible to WNV infection with a higher viral load in the brain than
wild-type (WT) control mice. The number of infiltrating WNV-specific CD8+
T cells and the expression levels of cytotoxicity mediators, such as
perforin, in the T cells in the brain of Il17rc-/- mice were reduced. In
addition, WNV-specific CD8+ T cells from IL-17RA deficient (Il17ra-/-)
mice and CD8+ cell-specific Il17ra conditional knockout (cre-KO) mice
expressed lower levels of perforin than their counterpart controls.
Moreover, supplementing mouse recombinant IL-17A ex vivo increased the
perforin production in WNV-specific CD8+ T cells from the WT mice but not
Il17rc-/- or cre-KO mice. Interestingly, we found that IL-17A signaling
activated the phosphatidylinositol-3-kinase/mammalian target of rapamycin
(PI3K-mTOR) signaling pathway in CD8+ T cells, leading to increased
metabolism of CD8+ T cells to cope with the higher energy demand for WNV
clearance in the brain. In summary, our findings reveal a novel
IL-17A-PI3K-mTOR signaling axis in promoting the effector functions of
CD8+ T cells, suggesting potential broader implications in stimulating
immune responses to combat WNV and other intracellular infections.