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 our...
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| Format: | Article |
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Public Library of Science (PLoS)
2025-07-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1013218 |
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| author | Farzana Nazneen Biswas Neupane Yao Chen Shazeed-Ul Karim Zongbing You Weiguo Cui Fengwei Bai |
| author_facet | Farzana Nazneen Biswas Neupane Yao Chen Shazeed-Ul Karim Zongbing You Weiguo Cui Fengwei Bai |
| author_sort | Farzana Nazneen |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-c899dac4d992453c8f02479bb7a7512f |
| institution | Kabale University |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS Pathogens |
| spelling | doaj-art-c899dac4d992453c8f02479bb7a7512f2025-08-20T03:56:00ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742025-07-01217e101321810.1371/journal.ppat.1013218Interleukin-17A signaling promotes CD8+ T cell cytotoxicity against West Nile virus infection through enhancing PI3K-mTOR-mediated metabolism.Farzana NazneenBiswas NeupaneYao ChenShazeed-Ul KarimZongbing YouWeiguo CuiFengwei BaiWest 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.https://doi.org/10.1371/journal.ppat.1013218 |
| spellingShingle | Farzana Nazneen Biswas Neupane Yao Chen Shazeed-Ul Karim Zongbing You Weiguo Cui Fengwei Bai Interleukin-17A signaling promotes CD8+ T cell cytotoxicity against West Nile virus infection through enhancing PI3K-mTOR-mediated metabolism. PLoS Pathogens |
| title | Interleukin-17A signaling promotes CD8+ T cell cytotoxicity against West Nile virus infection through enhancing PI3K-mTOR-mediated metabolism. |
| title_full | Interleukin-17A signaling promotes CD8+ T cell cytotoxicity against West Nile virus infection through enhancing PI3K-mTOR-mediated metabolism. |
| title_fullStr | Interleukin-17A signaling promotes CD8+ T cell cytotoxicity against West Nile virus infection through enhancing PI3K-mTOR-mediated metabolism. |
| title_full_unstemmed | Interleukin-17A signaling promotes CD8+ T cell cytotoxicity against West Nile virus infection through enhancing PI3K-mTOR-mediated metabolism. |
| title_short | Interleukin-17A signaling promotes CD8+ T cell cytotoxicity against West Nile virus infection through enhancing PI3K-mTOR-mediated metabolism. |
| title_sort | interleukin 17a signaling promotes cd8 t cell cytotoxicity against west nile virus infection through enhancing pi3k mtor mediated metabolism |
| url | https://doi.org/10.1371/journal.ppat.1013218 |
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