最近，发现TNF受体类型2（TNFR2）信号参与了调节性T细胞（Treg）的增殖和激活，Treg是一种能够抑制免疫反应的淋巴细胞亚群。Treg介导外周免疫耐受，其功能的破坏会导致自身免疫性疾病或过敏。因此，可以利用控制免疫抑制活性的Treg细胞扩展剂或调节剂来治疗这些疾病。我们关注于Treg上表达量相对较高的TNFR2，并创建了选择性激活小鼠和人类TNFR2信号传导的肿瘤坏死因子α（TNF-α）变种，分别称为R2agoTNF和R2-7。在本研究中，我们尝试通过单链同聚三聚体发动IgG-Fc融合来优化变种的结构，在体内增强它们的TNFR2激动活性和稳定性。融合蛋白scR2agoTNF-Fc可以增加CD4+CD25+ Treg和CD4+Foxp3+ Treg的增殖，并在小鼠模型中显著提高其体外和体内免疫抑制活性。预防性给予scR2agoTNF-Fc可以抑制接触性超敏反应和关节炎小鼠模型中的炎症。此外，scR2-7-Fc通过TNFR2可选择性扩展人类外周血单个核细胞中的Treg。这些具有双价结构的TNFR2激动剂-Fc融合蛋白是新型的Treg扩展剂。© 2023. Springer Nature Limited.

Recently, TNF receptor type 2 (TNFR2) signaling was found to be involved in the proliferation and activation of regulatory T cells (Tregs), a subpopulation of lymphocytes that suppress immune responses. Tregs mediate peripheral immune tolerance, and the disruption of their functions causes autoimmune diseases or allergy. Therefore, cell expanders or regulators of Tregs that control immunosuppressive activity can be used to treat these diseases. We focused on TNFR2, which is preferentially expressed on Tregs, and created tumor necrosis factor-α (TNF-α) muteins that selectively activate TNFR2 signaling in mice and humans, termed R2agoTNF and R2-7, respectively. In this study, we attempted to optimize the structure of muteins to enhance their TNFR2 agonistic activity and stability in vivo by IgG-Fc fusion following single-chain homo-trimerization. The fusion protein, scR2agoTNF-Fc, enhanced the expansion of CD4+CD25+ Tregs and CD4+Foxp3+ Tregs and contributed to their immunosuppressive activity ex vivo and in vivo in mice. The prophylactic administration of scR2agoTNF-Fc suppressed inflammation in contact hypersensitivity and arthritis mouse models. Furthermore, scR2-7-Fc preferentially expanded Tregs in human peripheral blood mononuclear cells via TNFR2. These TNFR2 agonist-Fc fusion proteins, which have bivalent structures, are novel Treg expanders.© 2023. Springer Nature Limited.