Endothelial progenitor cells (EPCs) are non-differentiated endothelial cells (ECs) present in blood circulation that are involved in neo-vascularization and correction of damaged endothelial sites. Since EPCs from patients with vascular disorders are impaired and inefficient, allogenic sources from adult or cord blood are considered as good alternatives. However, due to the reaction of immune system against allogenic cells which usually lead to their elimination, we focused on the exact role of EPCs on immune cells, particularly, T cells which are the most important cells applied in immune rejection. TNFα is one of the main activators of EPCs that recognizes two distinct receptors. TNFR1 is expressed ubiquitously and its interaction with TNFα leads to differentiation and apoptosis, whereas, TNFR2 is expressed predominantly on ECs, immune cells and neural cells and is involved in cell survival and proliferation. Interestingly, it has been shown that different immunosuppressive cells express TNFR2 and this is directly related to their immunosuppressive efficiency. However, little is known about immunological profile and function of TNFR2 in EPCs. Using different in-vitro combinations, we performed co-cultures of ECs and T cells to investigate the immunological effect of EPCs on T cells. We interrupted in the TNFα/TNFR2 axis either by blocking the receptor using TNFR2 antagonist or blocking the ligand using T cells derived from TNFα KO mice. We demonstrated that EPCs are able to suppress T cell proliferation and modulate them towards less pro-inflammatory and active phenotypes. Moreover, we showed that TNFα/TNFR2 immune-checkpoint pathway is critical in EPC immunomodulatory effect. Our results reveal for the first time a mechanism that EPCs use to suppress immune cells, therefore, enabling them to form new immunosuppressive vessels. Furthermore, we have shown the importance of TNFα/TNFR2 axis in EPCs as an immune checkpoint pathway. We believe that targeting TNFR2 is especially crucial in cancer immune therapy since it controls two crucial aspects of tumor microenvironment: 1) Immunosuppression and 2) Angiogenesis.

中文翻译：

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TNF/TNFR2信号通路是内皮祖细胞免疫抑制作用的关键调控因子。

内皮祖细胞 (EPC) 是存在于血液循环中的未分化内皮细胞 (EC)，参与新血管形成和修复受损内皮部位。由于来自血管疾病患者的 EPC 受损且效率低下，因此成人或脐带血的同种异体来源被认为是很好的替代品。然而，由于免疫系统对同种异体细胞的反应通常会导致它们被清除，我们专注于 EPCs 对免疫细胞的确切作用，特别是 T 细胞，这是应用于免疫排斥的最重要的细胞。TNFα 是识别两种不同受体的 EPC 的主要激活剂之一。TNFR1 普遍表达，其与 TNFα 的相互作用导致分化和凋亡，而 TNFR2 主要在 ECs 上表达，免疫细胞和神经细胞，参与细胞存活和增殖。有趣的是，已经表明不同的免疫抑制细胞表达 TNFR2，这与其免疫抑制效率直接相关。然而，关于 TNFR2 在 EPC 中的免疫学特征和功能知之甚少。使用不同的体外组合，我们进行了 EC 和 T 细胞的共培养，以研究 EPC 对 T 细胞的免疫学作用。我们通过使用 TNFR2 拮抗剂阻断受体或使用源自 TNFα KO 小鼠的 T 细胞阻断配体来中断 TNFα/TNFR2 轴。我们证明了 EPC 能够抑制 T 细胞增殖并将它们调节为较少的促炎和活性表型。而且，我们发现 TNFα/TNFR2 免疫检查点通路在 EPC 免疫调节作用中至关重要。我们的结果首次揭示了 EPC 用于抑制免疫细胞的机制，因此，使它们能够形成新的免疫抑制血管。此外，我们已经证明了 TNFα/TNFR2 轴在 EPC 中作为免疫检查点通路的重要性。我们认为靶向 TNFR2 在癌症免疫治疗中尤为重要，因为它控制着肿瘤微环境的两个关键方面：1) 免疫抑制和 2) 血管生成。