Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, Ministry of Education, Hefei, China.
Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China.
J Immunol. 2024 Mar 15;212(6):941-950. doi: 10.4049/jimmunol.2300442.
Tolerogenic dendritic cells are promising for restoring immune homeostasis and may be an alternative therapy for autoimmune diseases such as rheumatoid arthritis. The kynurenine pathway is a vital mechanism that induces tolerance in dendritic cells (DCs). Tryptophan 2,3-dioxygenase (TDO2) is an important rate-limiting enzyme in the kynurenine pathway and participates in immune regulation. However, the role of TDO2 in shaping the tolerogenic phenotypes of DCs remains unclear. In this study, we investigated the effects and mechanisms of TDO2-overexpressed DCs in regulating the T cell balance both in vivo and in vitro. TDO2-overexpressed DC2.4 and TDO2-/- mouse bone marrow-derived DCs (BMDCs) were generated to verify the role of TDO2 in DC maturation and functionality. TDO2 overexpression in BMDCs via PGE2 treatment exhibited an immature phenotype and tolerogenic state, whereas TDO2-/- BMDCs exhibited a mature phenotype and a proinflammatory state. Furthermore, transplant of TDO2-overexpressed BMDCs alleviated collagen-induced arthritis severity in mice, which was correlated with a reduction in Th17 populations and an increase in regulatory T cells. Collectively, these results indicate that TDO2 plays an important role in the tolerogenic phenotype and may be a promising target for the generation tolerogenic DCs for rheumatoid arthritis treatment.
诱导免疫耐受的树突状细胞有望恢复免疫稳态，可能成为类风湿关节炎等自身免疫性疾病的替代治疗方法。犬尿氨酸途径是诱导树突状细胞（DCs）耐受的重要机制。色氨酸 2,3-双加氧酶（TDO2）是犬尿氨酸途径中的重要限速酶，参与免疫调节。然而，TDO2 在塑造 DC 耐受表型中的作用尚不清楚。在这项研究中，我们研究了 TDO2 过表达的 DC 在体内和体外调节 T 细胞平衡的作用和机制。生成了 TDO2 过表达的 DC2.4 和 TDO2-/- 小鼠骨髓来源的树突状细胞（BMDCs），以验证 TDO2 在 DC 成熟和功能中的作用。通过 PGE2 处理过表达 BMDC 中的 TDO2 表现出不成熟表型和耐受状态，而 TDO2-/- BMDC 则表现出成熟表型和促炎状态。此外，移植 TDO2 过表达的 BMDC 可减轻胶原诱导性关节炎小鼠的严重程度，这与 Th17 细胞群减少和调节性 T 细胞增加相关。总之，这些结果表明 TDO2 在耐受表型中起重要作用，可能成为治疗类风湿关节炎的诱导耐受 DC 的有前途的靶点。
