VEGF-A enhances the cytotoxic function of CD4+ cytotoxic T cells via the VEGF-receptor 1/VEGF-receptor 2/AKT/mTOR pathway
Abstract Background CD4+ cytotoxic T cells (CD4 CTLs) are CD4+ T cells with major histocompatibility complex-II-restricted cytotoxic function. Under pathologic conditions, CD4 CTLs hasten the development of autoimmune disease or viral infection by enhancing cytotoxicity. However, the regulators of t...
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| Format: | Article |
| Language: | English |
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BMC
2023-02-01
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| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-023-03926-w |
| _version_ | 1811171579277606912 |
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| author | Ziyi Chen Meng Zhang Yufeng Liu Zhe Chen Ling Wang Wenjuan Wang Jincheng Wang Mingqian He Bingyin Shi Yue Wang |
| author_facet | Ziyi Chen Meng Zhang Yufeng Liu Zhe Chen Ling Wang Wenjuan Wang Jincheng Wang Mingqian He Bingyin Shi Yue Wang |
| author_sort | Ziyi Chen |
| collection | DOAJ |
| description | Abstract Background CD4+ cytotoxic T cells (CD4 CTLs) are CD4+ T cells with major histocompatibility complex-II-restricted cytotoxic function. Under pathologic conditions, CD4 CTLs hasten the development of autoimmune disease or viral infection by enhancing cytotoxicity. However, the regulators of the cytotoxicity of CD4 CTLs are not fully understood. Methods To explore the potential regulators of the cytotoxicity of CD4 CTLs, bulk RNA and single-cell RNA sequencing (scRNA-seq), enzyme-linked immunosorbent assay, flow cytometry, quantitative PCR, and in-vitro stimulation and inhibition assays were performed. Results In this study, we found that VEGF-A promoted the cytotoxicity of CD4 CTLs through scRNA-seq and flow cytometry. Regarding the specific VEGF receptor (R) involved, VEGF-R1/R2 signaling was activated in CD4 CTLs with increased cytotoxicity, and the VEGF-A effects were inhibited when anti-VEGF-R1/R2 neutralizing antibodies were applied. Mechanistically, VEGF-A treatment activated the AKT/mTOR pathway in CD4 CTLs, and the increases of cytotoxic molecules induced by VEGF-A were significantly reduced when the AKT/mTOR pathway was inhibited. Conclusion In conclusion, VEGF-A enhances the cytotoxicity of CD4 CTLs through the VEGF-R1/VEGF-R2/AKT/mTOR pathway, providing insights for the development of novel treatments for disorders associated with CD4 CTLs. |
| first_indexed | 2024-04-10T17:16:23Z |
| format | Article |
| id | doaj.art-9a74e09ed3df467bbaa4e493530e11fe |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-04-10T17:16:23Z |
| publishDate | 2023-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-9a74e09ed3df467bbaa4e493530e11fe2023-02-05T12:22:13ZengBMCJournal of Translational Medicine1479-58762023-02-0121111310.1186/s12967-023-03926-wVEGF-A enhances the cytotoxic function of CD4+ cytotoxic T cells via the VEGF-receptor 1/VEGF-receptor 2/AKT/mTOR pathwayZiyi Chen0Meng Zhang1Yufeng Liu2Zhe Chen3Ling Wang4Wenjuan Wang5Jincheng Wang6Mingqian He7Bingyin Shi8Yue Wang9Department of Endocrinology, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Endocrinology, The First Affiliated Hospital of Xi’an Jiaotong UniversityMOE Key Lab for Intelligent Networks & Networks Security, School of Electronic and Information Engineering, Xi’an Jiaotong UniversityDepartment of Spine Surgery, Hong Hui Hospital, Xi’an Jiaotong UniversityDepartment of Endocrinology, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Hematology, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Hematology, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Endocrinology, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Endocrinology, The First Affiliated Hospital of Xi’an Jiaotong UniversityDepartment of Endocrinology, The First Affiliated Hospital of Xi’an Jiaotong UniversityAbstract Background CD4+ cytotoxic T cells (CD4 CTLs) are CD4+ T cells with major histocompatibility complex-II-restricted cytotoxic function. Under pathologic conditions, CD4 CTLs hasten the development of autoimmune disease or viral infection by enhancing cytotoxicity. However, the regulators of the cytotoxicity of CD4 CTLs are not fully understood. Methods To explore the potential regulators of the cytotoxicity of CD4 CTLs, bulk RNA and single-cell RNA sequencing (scRNA-seq), enzyme-linked immunosorbent assay, flow cytometry, quantitative PCR, and in-vitro stimulation and inhibition assays were performed. Results In this study, we found that VEGF-A promoted the cytotoxicity of CD4 CTLs through scRNA-seq and flow cytometry. Regarding the specific VEGF receptor (R) involved, VEGF-R1/R2 signaling was activated in CD4 CTLs with increased cytotoxicity, and the VEGF-A effects were inhibited when anti-VEGF-R1/R2 neutralizing antibodies were applied. Mechanistically, VEGF-A treatment activated the AKT/mTOR pathway in CD4 CTLs, and the increases of cytotoxic molecules induced by VEGF-A were significantly reduced when the AKT/mTOR pathway was inhibited. Conclusion In conclusion, VEGF-A enhances the cytotoxicity of CD4 CTLs through the VEGF-R1/VEGF-R2/AKT/mTOR pathway, providing insights for the development of novel treatments for disorders associated with CD4 CTLs.https://doi.org/10.1186/s12967-023-03926-wCD4+ cytotoxic T cellsCD4 CTLsVEGF-AVEGF-R1VEGF-R2mTOR |
| spellingShingle | Ziyi Chen Meng Zhang Yufeng Liu Zhe Chen Ling Wang Wenjuan Wang Jincheng Wang Mingqian He Bingyin Shi Yue Wang VEGF-A enhances the cytotoxic function of CD4+ cytotoxic T cells via the VEGF-receptor 1/VEGF-receptor 2/AKT/mTOR pathway Journal of Translational Medicine CD4+ cytotoxic T cells CD4 CTLs VEGF-A VEGF-R1 VEGF-R2 mTOR |
| title | VEGF-A enhances the cytotoxic function of CD4+ cytotoxic T cells via the VEGF-receptor 1/VEGF-receptor 2/AKT/mTOR pathway |
| title_full | VEGF-A enhances the cytotoxic function of CD4+ cytotoxic T cells via the VEGF-receptor 1/VEGF-receptor 2/AKT/mTOR pathway |
| title_fullStr | VEGF-A enhances the cytotoxic function of CD4+ cytotoxic T cells via the VEGF-receptor 1/VEGF-receptor 2/AKT/mTOR pathway |
| title_full_unstemmed | VEGF-A enhances the cytotoxic function of CD4+ cytotoxic T cells via the VEGF-receptor 1/VEGF-receptor 2/AKT/mTOR pathway |
| title_short | VEGF-A enhances the cytotoxic function of CD4+ cytotoxic T cells via the VEGF-receptor 1/VEGF-receptor 2/AKT/mTOR pathway |
| title_sort | vegf a enhances the cytotoxic function of cd4 cytotoxic t cells via the vegf receptor 1 vegf receptor 2 akt mtor pathway |
| topic | CD4+ cytotoxic T cells CD4 CTLs VEGF-A VEGF-R1 VEGF-R2 mTOR |
| url | https://doi.org/10.1186/s12967-023-03926-w |
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