IL-17A Enhances CD8+ T Cell Metabolism to Restrict West Nile Virus in the Brain 2305958

Abstract Introduction West Nile virus (WNV) is the leading viral agent responsible for human neurological diseases in North America. Currently, there is no approved vaccine or specific treatment available for WNV infection or its neurological complications in humans. Our study suggested that interleukin-17A (IL-17A) plays a crucial role in regulating CD8 T cell cytotoxicity against WNV infection in the brain. In addition, our study has also revealed a novel function of IL-17A in activating 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 from the brain in mouse models; however, the underlying molecular mechanism remains unclear. Methods We used IL-17A signaling-deficient mice, RNA sequencing, and liquid chromatography-mass spectrometry (LC-MS/MS) approaches to identify key molecules that regulate the cytotoxicity and metabolism of CD8 T cells to meet the increased energy demand for WNV clearance in the brain. Results Our recent RNA-sequencing analysis suggests that the expression of TMPRSS3 (Transmembrane Serine Protease 3) is significantly reduced in CD8 T cells purified from both WNV-infected and uninfected IL-17 receptor C knockout (Il17rc-/-) mice compared to WT controls. TMPRSS3 has been implicated in cellular processes, including cell viability, apoptosis, and cancer progression, through modulating the PI3K/Akt/mTOR signaling pathway. Conclusion Our results indicate that IL-17A signaling may activate the PI3K-mTOR metabolic pathway via TMPRSS3, thereby exerting immune-therapeutic effects against WNV infection in the brain. Funding Source N/A Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)