Death Receptor 3 (DR3) is a cytokine receptor of the Tumor Necrosis Factor receptor superfamily that plays a multifaceted role in both innate and adaptive immunity. Based on the death domain motif in its cytosolic tail, DR3 had been proposed and functionally affirmed as a trigger of apoptosis. Further studies, however, also revealed roles of DR3 in other cellular pathways, including inflammation, survival, and proliferation. DR3 is expressed in various cell types, including T cells, B cells, innate lymphocytes, myeloid cells, fibroblasts, and even outside the immune system. Because DR3 is mainly expressed on T cells, DR3-mediated immune perturbations leading to autoimmunity and other diseases were mostly attributed to DR3 activation of T cells. However, which T cell subset and what T effector functions are controlled by DR3 to drive these processes remain incompletely understood. DR3 engagement was previously found to alter CD4 T helper subset differentiation, expand the Foxp3 Treg cell pool, and maintain intraepithelial γδ T cells in the gut. Recent studies further unveiled a previously unacknowledged aspect of DR3 in regulating innate-like invariant NKT (NKT) cell activation, expanding the scope of DR3-mediated immunity in T lineage cells. Importantly, in the context of NKT cells, DR3 ligation exerted costimulatory effects in agonistic TCR signaling, unveiling a new regulatory framework in T cell activation and proliferation. The current review is aimed at summarizing such recent findings on the role of DR3 on conventional T cells and innate-like T cells and discussing them in the context of immunopathogenesis.

中文翻译：

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细胞因子受体 DR3 在 T 细胞中的作用不断扩大

死亡受体 3 (DR3) 是肿瘤坏死因子受体超家族的细胞因子受体，在先天免疫和适应性免疫中发挥多方面的作用。基于其胞浆尾部的死亡结构域基序，DR3 被提出并在功能上被确认为细胞凋亡的触发因素。然而，进一步的研究还揭示了 DR3 在其他细胞途径中的作用，包括炎症、存活和增殖。DR3在多种细胞类型中表达，包括T细胞、B细胞、先天淋巴细胞、骨髓细胞、成纤维细胞，甚至免疫系统外。由于DR3主要在T细胞上表达，DR3介导的免疫扰动导致自身免疫和其他疾病大多归因于DR3对T细胞的激活。然而，哪些 T 细胞亚群和哪些 T 效应子功能由 DR3 控制来驱动这些过程仍不完全清楚。此前发现 DR3 参与可以改变 CD4 T 辅助子亚群分化、扩大 Foxp3 Treg 细胞库并维持肠道内上皮内 γδ T 细胞。最近的研究进一步揭示了 DR3 在调节先天性不变 NKT (NKT) 细胞激活方面先前未被承认的方面，扩大了 DR3 介导的 T 谱系细胞免疫的范围。重要的是，在 NKT 细胞中，DR3 连接在激动性 TCR 信号传导中发挥共刺激作用，揭示了 T 细胞激活和增殖的新调控框架。本综述旨在总结 DR3 对常规 T 细胞和先天样 T 细胞作用的最新发现，并在免疫发病机制的背景下对其进行讨论。