EBI2 contributes to the induction of thymic central tolerance in mice by promoting rapid motility of medullary thymocytes.
EBI2 contributes to the induction of thymic central tolerance in mice by promoting rapid motility of medullary thymocytes.
复制标题
EBI2 通过促进髓质胸腺细胞的快速运动，有助于诱导小鼠胸腺中枢耐受。
DOI：
10.1002/eji.201747020
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发表时间：
2017
影响因子：
5.4
通讯作者：
Ehrlich,LaurenIR
中科院分区：
文献类型：
--
作者：
Ki,Sanghee;Thyagarajan,HiranM;Hu,Zicheng;Lancaster,JessicaN;Ehrlich,LaurenIR
成熟的胸腺细胞进入胸腺髓质，在那里它们遇到由抗原呈递细胞（APC）呈递的许多自身抗原。那些具有强烈自身反应性的胸腺细胞经历负选择或转向为调节性T细胞谱系。虽然大多数蛋白质组在髓质中表达，但许多自身抗原仅由一小部分髓质APC表达;因此，胸腺细胞必须有效地进入髓质并扫描APC以确保中枢耐受。趋化因子受体促进淋巴细胞迁移、组织内组织化以及与淋巴器官中APC的相互作用。趋化因子受体EBI 2在次级淋巴器官中的免疫应答期间支配T细胞、B细胞和树突状细胞（DC）的定位。然而，EBI 2在胸腺细胞发育中的作用尚未阐明。在这里，我们证明EBI 2表达的小鼠CD 4+单阳性（CD 4SP）胸腺细胞和胸腺DC。EBI 2缺陷改变TCR库，但不严重影响胸腺细胞的细胞结构或亚群分布。EBI 2缺陷也损害响应内源性自身抗原的OT-II TCR转基因胸腺细胞的阴性选择。双光子成像显示，EBI 2缺乏导致CD 4SP胸腺细胞迁移减少和髓质蓄积受损。这些数据确定了EBI 2在促进有效的胸腺中枢耐受中的作用。
Maturing thymocytes enter the thymic medulla, where they encounter numerous self‐antigens presented by antigen presenting cells (APCs). Those thymocytes that are strongly self‐reactive undergo either negative selection or diversion into the regulatory T‐cell lineage. Although the majority of the proteome is expressed in the medulla, many self‐antigens are expressed by only a minor fraction of medullary APCs; thus, thymocytes must efficiently enter the medulla and scan APCs to ensure central tolerance. Chemokine receptors promote lymphocyte migration, organization within tissues, and interactions with APCs in lymphoid organs. The chemokine receptor EBI2 governs localization of T cells, B cells, and dendritic cells (DCs) during immune responses in secondary lymphoid organs. However, the role of EBI2 in thymocyte development has not been elucidated. Here, we demonstrate that EBI2 is expressed by murine CD4+single positive (CD4SP) thymocytes and thymic DCs. EBI2 deficiency alters the TCR repertoire, but does not grossly impact thymocyte cellularity or subset distribution. EBI2 deficiency also impairs negative selection of OT‐II TCR transgenic thymocytes responding to an endogenous self‐antigen. Two‐photon imaging revealed that EBI2 deficiency results in reduced migration and impaired medullary accumulation of CD4SP thymocytes. These data identify a role for EBI2 in promoting efficient thymic central tolerance.