Ubiquitin ligase MARCH 8 cooperates with CD83 to control surface MHC II expression in thymic epithelium and CD4 T cell selection.
Ubiquitin ligase MARCH 8 cooperates with CD83 to control surface MHC II expression in thymic epithelium and CD4 T cell selection.
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DOI：
10.1084/jem.20160312
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发表时间：
2016-08-22
期刊：
影响因子：
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通讯作者：
Mintern JD
中科院分区：
文献类型：
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作者：
Liu H;Jain R;Guan J;Vuong V;Ishido S;La Gruta NL;Gray DH;Villadangos JA;Mintern JD
Mintern、Villadangos及其同事发现，3月8日在胸腺上皮细胞表面MHC II表达的翻译后调节中发挥作用，这对CD4+T细胞的选择具有重要意义。主要组织相容性复合体II类(MHC II)的表达受到严格调控，受到细胞类型特异性机制的影响，这些机制密切控制其在细胞表面的水平。E3泛素连接酶3月1泛素化调节树突状细胞和B细胞中MHC II的表达。在这项研究中，我们证明了相关的连接酶3月8日负责调节胸腺上皮细胞(TECs)的表面MHC II。−/−小鼠皮质TECs和自身免疫调节因子(AIRE)−延髓TECs表面MHC II均升高，但AIRE+MTECs无明显变化。尽管如此，胸腺和脾中CD_4~+T细胞的数量和谱系在3月8日的−/−小鼠中保持不变。值得注意的是，MHC II在3月8日之前的泛素化受CD83控制。表达CD83突变形式的小鼠(CD83anu/ANU小鼠)损害了CD4+T细胞的选择，但在CD83anu/ANU小鼠中，缺失March8使CD4+T细胞选择恢复到正常水平。因此，3月8日和CD83对TECs表面MHC II表达的协同调节在CD4+T细胞的选择中起着重要作用。我们的结果也强调了泛素化机制在不同的抗原提呈细胞类型中的专门使用，具有重要的功能后果和对治疗操作的影响。
Mintern, Villadangos, and colleagues show that MARCH 8 plays a role in the posttranslational regulation of surface MHC II expression in thymic epithelial cells, with important implications for CD4+ T cell selection. Major histocompatibility complex class II (MHC II) expression is tightly regulated, being subjected to cell type–specific mechanisms that closely control its levels at the cell surface. Ubiquitination by the E3 ubiquitin ligase MARCH 1 regulates MHC II expression in dendritic cells and B cells. In this study, we demonstrate that the related ligase MARCH 8 is responsible for regulating surface MHC II in thymic epithelial cells (TECs). March8−/− mice have elevated MHC II at the surface of cortical TECs and autoimmune regulator (AIRE)− medullary TECs (mTECs), but not AIRE+ mTECs. Despite this, thymic and splenic CD4+ T cell numbers and repertoires remained unaltered in March8−/− mice. Notably, the ubiquitination of MHC II by MARCH 8 is controlled by CD83. Mice expressing a mutated form of CD83 (Cd83anu/anu mice) have impaired CD4+ T cell selection, but deleting March8 in Cd83anu/anu mice restored CD4+ T cell selection to normal levels. Therefore, orchestrated regulation of MHC II surface expression in TECs by MARCH 8 and CD83 plays a major role in CD4+ T cell selection. Our results also highlight the specialized use of ubiquitinating machinery in distinct antigen-presenting cell types, with important functional consequences and implications for therapeutic manipulation.