Interleukin-17A Promotes CD8⁺T Cell Cytotoxicity To Facilitate West Nile Virus Clearance

Abstract

CD8 ϩ T cells are crucial components of immunity and play a vital role in recovery from West Nile virus (WNV) infection. Here, we identify a previously unrecognized function of interleukin-17A (IL-17A) in inducing cytotoxic-mediator gene expression and promoting CD8 ϩ T cell cytotoxicity against WNV infection in mice. We find that IL-17A-deficient (Il17a Ϫ/Ϫ ) mice are more susceptible to WNV infection and develop a higher viral burden than wild-type (WT) mice. Interestingly, the CD8 ϩ T cells isolated from Il17a Ϫ/Ϫ mice are less cytotoxic and express lower levels of cytotoxic-mediator genes, which can be restored by supplying recombinant IL-17A in vitro and in vivo. Importantly, treatment of WNV-infected mice with recombinant IL-17A, as late as day 6 postinfection, significantly reduces the viral burden and increases survival, suggesting a therapeutic potential for IL-17A. In conclusion, we report a novel function of IL-17A in promoting CD8 ϩ T cell cytotoxicity, which may have broad implications in other microbial infections and cancers.IMPORTANCE Interleukin-17A (IL-17A) and CD8 ϩ T cells regulate diverse immune functions in microbial infections, malignancies, and autoimmune diseases. IL-17A is a proinflammatory cytokine produced by diverse cell types, while CD8 ϩ T cells (known as cytotoxic T cells) are major cells that provide immunity against intracellular pathogens. Previous studies have demonstrated a crucial role of CD8 ϩ T cells in recovery from West Nile virus (WNV) infection. However, the role of IL-17A during WNV infection remains unclear. Here, we demonstrate that IL-17A protects mice from lethal WNV infection by promoting CD8 ϩ T cell-mediated clearance of WNV. In addition, treatment of WNV-infected mice with recombinant IL-17A reduces the viral burden and increases survival of mice, suggesting a potential therapeutic. This novel IL-17A-CD8 ϩ T cell axis may also have broad implications for immunity to other microbial infections and cancers, where CD8 ϩ T cell functions are crucial.

Activated CD8+ T Cells Cause Long-Term Neurological Impairment after Traumatic Brain Injury in Mice

“…Th17-like cells/responses (e.g., IL-17A, IL-21) can enhance the cytotoxicity of CD8 + T cells by enhancing GrB (and A) gene expression, as shown in other conditions (Acharya et al, 2016;Duan et al, 2012). That we observed an increase in IL-17 and IFN-g-producing CD4 + T cells in the brain at 1 week post-TBI, which preceded the increase in GrB + CD8 + T cells at 8 weeks, suggests that Th17 cells may be driving the cytotoxicity of CD8 + T cells.…”

In Vitro Th17-Polarized Human CD4+ T Cells Exacerbate Xenogeneic Graft-versus-Host Disease

“…However, we did not observe higher chimerism in PB at days +14 and +21 in Th17 coinjected mice. Data from antitumor and antiviral immunity experiments have also revealed that Th17 cells could have a unique ability to promote CD8 + T cell priming and cytotoxicity in target tissues through both direct [52][53][54] and indirect (via the recruitment of dendritic cells) [52,55] mechanisms.…”

Current Understanding of West Nile Virus Clinical Manifestations, Immune Responses, Neuroinvasion, and Immunotherapeutic Implications

“…A study showed that antagonism of CXCR4 significantly improved survival through enhanced intraparenchymal migration of WNV-specific CD8 + T cells within the brain [117]. Moreover, enhanced CD8 + T cells cytotoxicity through a supplement of IL-17A has been shown to increase the survival of the mice from WNV infection [118]. Collectively, the results from these studies indicated that CD8 + T cells play an important protective role in controlling WNV infection.…”

“…Although induction of neuroinflammation is necessary for defense against many viral infections, including other flaviviruses, it is also recognized as a potential contributor to neuropathogenesis [159][160][161]. Moreover, levels of some cytokines including IL-2, IL-6, IL-12, granulocyte-macrophage colony-stimulating factor (GM-CSF), IFN-γ, IFN-γ induced protein 10 (IP-10), IL-17A and OPN [30,78,118], have been reported to be elevated for months to years following the recovery of acute illness, leading to a post-infectious proinflammatory state that may contribute to long-term neuroinflammation in WNV survivors [30,78,118]. Among a large cohort of participants with a history of WNV infection in Houston, TX, USA, approximately 40% of those who presented with clinical disease continued to experience WNV-related morbidity up to eight years post-infection [162].…”