CD69 acts downstream of interferon-α/β to inhibit S1P1 and lymphocyte egress from lymphoid organs
CD69 acts downstream of interferon-α/β to inhibit S1P1 and lymphocyte egress from lymphoid organs
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DOI：
10.1038/nature04606
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发表时间：
2006-03-23
期刊：
影响因子：
64.8
通讯作者：
Matloubian, M
中科院分区：
文献类型：
--
作者：
Shiow, LR;Rosen, DB;Matloubian, M
幼稚淋巴细胞在再循环过程中不断进出淋巴器官，这对于免疫监视至关重要。在免疫反应期间，出口进程可能会暂时关闭(1)。当这种情况发生在局部时，反应淋巴器官中的淋巴细胞数量就会增加；当它全身发生时，由于再循环淋巴细胞的消耗，可能会导致免疫抑制。已知先天免疫系统的几种介质会导致关闭，包括干扰素 α/β (IFN-α/β) 和肿瘤坏死因子 (2-5)，但其机制尚不清楚。在这里，我们表明，用 IFN-α/β 诱导剂聚肌苷多胞苷酸（以下简称“聚（I：C）”）治疗通过部分淋巴细胞固有的机制抑制了流出。 Poly(I:C)处理或淋巴细胞性脉络丛脑膜炎病毒感染后，跨膜C型凝集素CD69被迅速诱导，CD69(-/-)细胞在淋巴组织中保留不良。淋巴细胞的排出需要鞘氨醇 1-磷酸受体-1 (S1P(1))，并且发现 IFN-α/β 可以抑制淋巴细胞对 S1P 的反应。相比之下，CD69(-/-)细胞在暴露于IFN-α/β后保留了S1P(1)功能。在共表达实验中，CD69 抑制 S1P(1) 趋化功能并导致 S1P(1) 下调。在报告基因检测中，S1P(1) 交联导致 CD69-CD3 zeta 嵌合体的共交联和激活。 CD69 与 S1P(1) 共免疫沉淀，但不与相关受体 S1P(3) 共免疫沉淀。这些观察结果表明，CD69 与 S1P(1) 形成复合物并对 S1P(1) 进行负调节，并且它在 IFN-α/β 以及可能的其他激活刺激物的下游发挥作用，以促进淋巴细胞在淋巴器官中的滞留。
Naive lymphocytes continually enter and exit lymphoid organs in a recirculation process that is essential for immune surveillance. During immune responses, the egress process can be shut down transiently(1). When this occurs locally it increases lymphocyte numbers in the responding lymphoid organ; when it occurs systemically it can lead to immunosuppression as a result of the depletion of recirculating lymphocytes. Several mediators of the innate immune system are known to cause shutdown, including interferon alpha/beta (IFN-alpha/beta) and tumour necrosis factor(2-5), but the mechanism has been unclear. Here we show that treatment with the IFN-alpha/beta inducer polyinosine polycytidylic acid (hereafter 'poly(I:C)') inhibited egress by a mechanism that was partly lymphocyte-intrinsic. The transmembrane C-type lectin CD69 was rapidly induced and CD69(-/-) cells were poorly retained in lymphoid tissues after treatment with poly(I:C) or infection with lymphocytic choriomeningitis virus. Lymphocyte egress requires sphingosine 1-phosphate receptor-1 (S1P(1)), and IFN-alpha/beta was found to inhibit lymphocyte responsiveness to S1P. By contrast, CD69(-/-) cells retained S1P(1) function after exposure to IFN-alpha/beta. In coexpression experiments, CD69 inhibited S1P(1) chemotactic function and led to downmodulation of S1P(1). In a reporter assay, S1P(1) crosslinking led to co-crosslinking and activation of a CD69-CD3 zeta chimaera. CD69 co-immunoprecipitated with S1P(1) but not the related receptor, S1P(3). These observations indicate that CD69 forms a complex with and negatively regulates S1P(1) and that it functions downstream of IFN-alpha/beta, and possibly other activating stimuli, to promote lymphocyte retention in lymphoid organs.