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

## TL;DR

This study shows that IL-17A signaling boosts CD8+ T cell energy metabolism, helping fight West Nile virus in the brain.

## Contribution

The study reveals a novel IL-17A-PI3K-mTOR signaling axis that enhances CD8+ T cell metabolism during West Nile virus infection.

## Key findings

- IL-17RC deficient mice showed increased WNV susceptibility and lower CD8+ T cell infiltration in the brain.
- IL-17A signaling activates PI3K-mTOR pathway in CD8+ T cells, enhancing their metabolism for WNV clearance.
- Perforin expression in CD8+ T cells is reduced in IL-17RA and IL-17RC deficient mice.

## Abstract

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.

West Nile encephalitis is the leading viral neurological disease in the United States and North America. No approved vaccine or specific therapeutics are available to prevent or treat human West Nile virus (WNV) infection. Interleukin 17A (IL-17A) is a pleiotropic cytokine that regulates inflammatory diseases and cancers. One of our previous studies has demonstrated that IL-17A signaling promotes the cytotoxicity of CD8+ T cells and facilitates WNV clearance from the brain in the mouse model, as well as the therapeutic potential of this cytokine. However, the molecular mechanism is not understood. This study uncovered a new role of IL-17A signaling in activating a metabolic pathway in CD8+ T cells to cope with the higher energy demand for WNV clearance from the brain. This finding may have broader therapeutic implications in stimulating IL-17A-mediated metabolic pathways in CD8+ T cells to combat other viral and intracellular infections.