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首页> 外文期刊>Nature >CD69 acts downstream of interferon-alpha/beta to inhibit S1P1 and lymphocyte egress from lymphoid organs.
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CD69 acts downstream of interferon-alpha/beta to inhibit S1P1 and lymphocyte egress from lymphoid organs.

机译：CD69在干扰素-α/β的下游起作用，以抑制S1P1和淋巴细胞从淋巴器官中流出。

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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. 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, 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 (S1P1), and IFN-alpha/beta was found to inhibit lymphocyte responsiveness to S1P. By contrast, CD69-/- cells retained S1P1 function after exposure to IFN-alpha/beta. In coexpression experiments, CD69 inhibited S1P1 chemotactic function and led to downmodulation of S1P1. In a reporter assay, S1P1 crosslinking led to co-crosslinking and activation of a CD69-CD3zeta chimaera. CD69 co-immunoprecipitated with S1P1 but not the related receptor, S1P3. These observations indicate that CD69 forms a complex with and negatively regulates S1P1 and that it functions downstream of IFN-alpha/beta, and possibly other activating stimuli, to promote lymphocyte retention in lymphoid organs.
机译：幼稚的淋巴细胞在循环过程中不断进入和离开淋巴器官，这对免疫监视至关重要。在免疫反应期间，可以暂时关闭出口过程。当这种情况局部发生时，它会增加响应的淋巴器官中的淋巴细胞数量。当它全身发生时，由于再循环淋巴细胞的耗尽，可能导致免疫抑制。已知先天免疫系统的几种介体会引起关闭，包括干扰素α/β（IFN-α/β）和肿瘤坏死因子，但机制尚不清楚。在这里，我们表明用IFN-α/β诱导剂多肌苷聚胞苷酸（以下简称“ poly（I：C）”）进行的治疗通过部分淋巴细胞固有的机制抑制了出口。经聚（I：C）处理或感染了淋巴细胞性脉络膜脑膜炎病毒后，跨膜C型凝集素CD69迅速被诱导，CD69-/-细胞在淋巴组织中的保留能力很差。淋巴细胞流出需要1磷酸鞘氨醇受体1（S1P1），并且发现IFN-α/β抑制淋巴细胞对S1P的响应。相反，CD69-/-细胞在暴露于IFN-α/β后仍保留S1P1功能。在共表达实验中，CD69抑制S1P1趋化功能并导致S1P1的下调。在报道分子测定中，S1P1交联导致CD69-CD3zeta chimaera的共交联和活化。 CD69与S1P1共免疫沉淀，但不与相关受体S1P3免疫沉淀。这些观察结果表明，CD69与S1P1形成复合物并对其负调控，并且它在IFN-α/β以及可能的其他激活刺激物的下游起作用，以促进淋巴细胞在淋巴器官中的滞留。

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