2. Academic Validation
  3. VEGF-A enhances the cytotoxic function of CD4+ cytotoxic T cells via the VEGF-receptor 1/VEGF-receptor 2/AKT/mTOR pathway

VEGF-A enhances the cytotoxic function of CD4+ cytotoxic T cells via the VEGF-receptor 1/VEGF-receptor 2/AKT/mTOR pathway

  • J Transl Med. 2023 Feb 3;21(1):74. doi: 10.1186/s12967-023-03926-w.
Ziyi Chen # 1,  Meng Zhang # 1,  Yufeng Liu 2 3 4,  Zhe Chen 5,  Ling Wang 1,  Wenjuan Wang 6,  Jincheng Wang 6,  Mingqian He 1,  Bingyin Shi 7,  Yue Wang 8 9 10
Affiliations

Affiliations

  • 1 Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
  • 2 MOE Key Lab for Intelligent Networks & Networks Security, School of Electronic and Information Engineering, Xi'an Jiaotong University, Xi'an, China.
  • 3 Genome Institute, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
  • 4 BioBank, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
  • 5 Department of Spine Surgery, Hong Hui Hospital, Xi'an Jiaotong University, Xi'an, China.
  • 6 Department of Hematology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
  • 7 Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. shibingy@126.com.
  • 8 Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. shelly1021@126.com.
  • 9 MOE Key Lab for Intelligent Networks & Networks Security, School of Electronic and Information Engineering, Xi'an Jiaotong University, Xi'an, China. shelly1021@126.com.
  • 10 Genome Institute, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China. shelly1021@126.com.
  • # Contributed equally.
PMID: 36737819 DOI: 10.1186/s12967-023-03926-w
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.

Keywords

CD4 CTLs; CD4+ cytotoxic T cells; Graves orbitopathy; VEGF-A; VEGF-R1; VEGF-R2; mTOR.

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