VEGF-A 通过 VEGF 受体 1/VEGF 受体 2/AKT/mTOR 通路增强 CD4 细胞毒性 T 细胞的细胞毒性功能。

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

机构信息

Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

MOE Key Lab for Intelligent Networks & Networks Security, School of Electronic and Information Engineering, Xi'an Jiaotong University, Xi'an, China.

出版信息

J Transl Med. 2023 Feb 3;21(1):74. doi: 10.1186/s12967-023-03926-w.

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.

背景

CD4 细胞毒性 T 细胞（CD4 CTLs）是具有主要组织相容性复合体-II 限制细胞毒性功能的 CD4 T 细胞。在病理条件下，CD4 CTLs 通过增强细胞毒性，加速自身免疫性疾病或病毒感染的发展。然而，CD4 CTLs 细胞毒性的调节因子尚未完全阐明。

方法

为了探索 CD4 CTLs 细胞毒性的潜在调节因子，进行了批量 RNA 和单细胞 RNA 测序（scRNA-seq）、酶联免疫吸附测定、流式细胞术、定量 PCR 以及体外刺激和抑制实验。

结果

在这项研究中，我们发现 VEGF-A 通过 scRNA-seq 和流式细胞术促进 CD4 CTLs 的细胞毒性。关于涉及的特定 VEGF 受体（R），在细胞毒性增加的 CD4 CTLs 中激活了 VEGF-R1/R2 信号通路，并且当应用抗 VEGF-R1/R2 中和抗体时，VEGF-A 的作用被抑制。在机制上，VEGF-A 处理激活了 CD4 CTLs 中的 AKT/mTOR 通路，并且当 AKT/mTOR 通路被抑制时，VEGF-A 诱导的细胞毒性分子的增加显著降低。