MerTK is required for apoptotic cell-induced T cell tolerance.
MerTK is required for apoptotic cell-induced T cell tolerance.
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MERTK是凋亡细胞诱导的T细胞耐受性所必需的。
DOI：
10.1084/jem.20062293
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发表时间：
2008-01-21
影响因子：
15.3
通讯作者：
Tisch, Roland
中科院分区：
文献类型：
--
作者：
Wallet, Mark A.;Sen, Pradip;Flores, Rafael R.;Wang, Yaming;Yi, Zuoan;Huang, Yingsu;Mathews, Clayton E.;Earp, H. Shelton;Matsushima, Glenn;Wang, Bo;Tisch, Roland
凋亡细胞表达的自身抗原可能成为自身免疫的靶点。对这些抗原的耐受性部分是由AC抑制抗原呈递细胞如树突状细胞（DC）的不明确的能力建立的。我们目前的证据表明，受体酪氨酸激酶Mer（MerTK）在介导AC诱导的DC激活/成熟抑制中起关键作用。用AC预处理从非肥胖糖尿病（NOD）小鼠制备的DC，阻断促炎细胞因子的分泌、共刺激分子表达的上调和T细胞活化。AC对DC的作用依赖于Gas 6，其是MerTK配体。缺乏MerTK表达的NOD DC（NOD.MerTKKD/KD）对AC诱导的抑制具有抗性。值得注意的是，自身免疫性糖尿病在表达转基因BDC T细胞受体的NOD、MerTKKD/KD与NOD小鼠中加重。此外，β细胞特异性CD 4 + T细胞过继转移到NOD.MerTKKD/KD小鼠中，其中β细胞凋亡用链脲佐菌素诱导，表现出增加的扩增和分化为1型T细胞效应器。在两种模型中，MerTK表达的缺乏与活化的胰腺CD 11 c + CD 8 α+ DC的频率增加相关，其表现出增强的T细胞刺激能力。这些发现表明MerTK在调节AC、DC和T细胞之间介导的自身耐受中起关键作用。
Self-antigens expressed by apoptotic cells (ACs) may become targets for autoimmunity. Tolerance to these antigens is partly established by an ill-defined capacity of ACs to inhibit antigen-presenting cells such as dendritic cells (DCs). We present evidence that the receptor tyrosine kinase Mer (MerTK) has a key role in mediating AC-induced inhibition of DC activation/maturation. Pretreatment of DCs prepared from nonobese diabetic (NOD) mice with AC blocked secretion of proinflammatory cytokines, up-regulation of costimulatory molecule expression, and T cell activation. The effect of ACs on DCs was dependent on Gas6, which is a MerTK ligand. NOD DCs lacking MerTK expression (NOD.MerTKKD/KD) were resistant to AC-induced inhibition. Notably, autoimmune diabetes was exacerbated in NOD.MerTKKD/KD versus NOD mice expressing the transgenic BDC T cell receptor. In addition, β cell–specific CD4+ T cells adoptively transferred into NOD.MerTKKD/KD mice in which β cell apoptosis was induced with streptozotocin exhibited increased expansion and differentiation into type 1 T cell effectors. In both models, the lack of MerTK expression was associated with an increased frequency of activated pancreatic CD11c+CD8α+ DCs, which exhibited an enhanced T cell stimulatory capacity. These findings demonstrate that MerTK plays a critical role in regulating self-tolerance mediated between ACs, DCs, and T cells.
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