Wallet Mark A, Flores Rafael R, Wang Yaming, Yi Zuoan, Kroger Charles J, Mathews Clayton E, Earp H Shelton, Matsushima Glenn, Wang Bo, Tisch Roland
Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599-7020, USA.
Proc Natl Acad Sci U S A. 2009 Mar 24;106(12):4810-5. doi: 10.1073/pnas.0900683106. Epub 2009 Feb 27.
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 beta cell-specific T cells independent of immunoregulatory effectors. The establishment of bone marrow chimeric mice demonstrated that the block in beta 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 beta cell autoimmunity.
诸如1型糖尿病（T1D）等T细胞介导的自身免疫性疾病被认为部分是由于自身特异性胸腺细胞的阴性选择效率低下所致。然而，调节胸腺阴性选择的事件尚未完全明确。在本研究中，我们证明缺乏Mer酪氨酸激酶（MerTK）表达的非肥胖糖尿病（NOD）小鼠胰岛炎症减轻且不会患糖尿病。此外，缺乏MerTK表达的NOD小鼠（Mer(-/-)）表现出β细胞特异性T细胞频率降低，且与免疫调节效应物无关。骨髓嵌合小鼠的建立表明，β细胞自身免疫的阻断需要缺乏MerTK表达的造血来源细胞。值得注意的是，胎儿胸腺器官培养和自身肽给药显示Mer(-/-)小鼠的胸腺阴性选择增加。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介导的胸腺细胞阴性选择和胸腺DC调节的独特机制提供了证据，并提示MerTK在促成β细胞自身免疫中发挥作用。
