The TNF-family receptor DR3 is essential for diverse T cell-mediated inflammatory diseases
The TNF-family receptor DR3 is essential for diverse T cell-mediated inflammatory diseases
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DOI：
10.1016/j.immuni.2008.04.021
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发表时间：
2008-07-18
期刊：
影响因子：
32.4
通讯作者：
Siegel, Richard M.
中科院分区：
文献类型：
--
作者：
Meylan, Francoise;Davidson, Todd S.;Siegel, Richard M.
DR 3（TRAMP、LARD、WSL-1、TNFRSF 25）是主要在T细胞上表达的含有死亡结构域的肿瘤坏死因子（TNF）家族受体。TL 1A是DR 3的TNF家族配体，可以共刺激T细胞，但TL 1A-DR 3相互作用在免疫应答中的生理功能尚不清楚。使用DR 3缺陷小鼠，我们确定DR 3作为负责TL 1A诱导的T细胞共刺激的受体，树突状细胞作为TL 1A在T细胞活化过程中的可能来源。尽管其在共刺激中的作用，DR 3是不需要在体内T细胞引发，极化成辅助性T细胞1（Th 1），Th 2，或Th 17效应细胞亚型，或有效控制感染弓形虫。相反，在实验性自身免疫性脑脊髓炎（EAE）和过敏性肺部炎症（依赖于不同效应T细胞亚群的疾病模型）中，T细胞上需要DR 3表达用于免疫病理学、局部T细胞积累和细胞因子产生。DR 3可能是T细胞介导的自身免疫性和过敏性疾病的一个有吸引力的治疗靶点。
DR3 (TRAMP, LARD, WSL-1, TNFRSF25) is a death-domain-containing tumor necrosis factor (TNF)family receptor primarily expressed on T cells. TL1A, the TNF-family ligand for DR3, can costimulate T cells, but the physiological function of TL1A-DR3 interactions in immune responses is not known. Using DR3-deficient mice, we identified DR3 as the receptor responsible for TL1A-induced T cell costimulation and dendritic cells as the likely source for TL1A during T cell activation. Despite its role in costimulation, DR3 was not required for in vivo T cell priming, for polarization into T helper 1 (Th1), Th2, or Th17 effector cell subtypes, or for effective control of infection with Toxoplasma gondii. Instead, DR3 expression was required on T cells for immunopathology, local T cell accumulation, and cytokine production in Experimental Autoimmune Encephalomyelitis (EAE) and allergic lung inflammation, disease models that depend on distinct effector T cell subsets. DR3 could be an attractive therapeutic target for T cell-mediated autoimmune and allergic diseases.