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.
Copyright: © 2025 Nazneen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.