MerTK regulates thymic selection of autoreactive T cells.
MerTK regulates thymic selection of autoreactive T cells.
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MerTK 调节自身反应性 T 细胞的胸腺选择。
DOI：
10.1073/pnas.0900683106
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发表时间：
2009
影响因子：
11.1
通讯作者：
Tisch,Roland
中科院分区：
文献类型：
--
作者：
Wallet,MarkA;Flores,RafaelR;Wang,Yaming;Yi,Zuoan;Kroger,CharlesJ;Mathews,ClaytonE;Earp,HShelton;Matsushima,Glenn;Wang,Bo;Tisch,Roland
T细胞介导的自身免疫性疾病如1型糖尿病（T1 D）被认为是自身特异性胸腺细胞的无效负选择的部分结果。然而，调节胸腺负选择的事件尚未完全了解。在目前的研究中，我们证明了缺乏Mer酪氨酸激酶（MerTK）表达的非肥胖糖尿病（NOD）小鼠的胰岛炎症减少，不会发生糖尿病。此外，MerTK表达缺陷的NOD小鼠（Mer−/−）表现出β细胞特异性T细胞的频率降低，与免疫调节效应无关。骨髓嵌合体小鼠的建立表明，β细胞自身免疫的阻断需要缺乏MerTK表达的造血源性细胞。值得注意的是，胎儿胸腺器官培养和自身肽给药显示Mer−/−小鼠胸腺阴性选择增加。最后，从Mer−/−小鼠制备的胸腺树突状细胞（DC）在体外以肽特异性方式诱导胸腺细胞凋亡的能力增强。这些发现为涉及MerTK介导的胸腺细胞负选择和胸腺DC调节的独特机制提供了证据，并表明MerTK在促进β细胞自身免疫中的作用。
T cell-mediated autoimmune diseases such as type 1 diabetes (T1D) are believed to be the result in part of inefficient negative selection of self-specific thymocytes. However, the events regulating thymic negative selection are not fully understood. In the current study, we demonstrate that nonobese diabetic (NOD) mice lacking expression of the Mer tyrosine kinase (MerTK) have reduced inflammation of the pancreatic islets and fail to develop diabetes. Furthermore, NOD mice deficient in MerTK expression (Mer−/−) exhibit a reduced frequency of β cell-specific T cells independent of immunoregulatory effectors. The establishment of bone marrow chimeric mice demonstrated that the block in β cell autoimmunity required hematopoietic-derived cells lacking MerTK expression. Notably, fetal thymic organ cultures and self-peptide administration showed increased thymic negative selection in Mer−/−mice. Finally, thymic dendritic cells (DC) prepared from Mer−/−mice exhibited an increased capacity to induce thymocyte apoptosis in a peptide-specific manner in vitro. These findings provide evidence for a unique mechanism involving MerTK-mediated regulation of thymocyte negative selection and thymic DC, and suggest a role for MerTK in contributing to β cell autoimmunity.