Interchangeability of Themis1 and Themis2 in Thymocyte Development Reveals Two Related Proteins with Conserved Molecular Function
Interchangeability of Themis1 and Themis2 in Thymocyte Development Reveals Two Related Proteins with Conserved Molecular Function
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DOI：
10.4049/jimmunol.1200123
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发表时间：
2012-08-01
影响因子：
4.4
通讯作者：
Love, Paul E.
中科院分区：
文献类型：
--
作者：
Lesourne, Renaud;Zvezdova, Ekaterina;Love, Paul E.
Themis 1是最近发现的一种T细胞蛋白，在成熟的CD 4（+）CD 8（-）和CD 4（-）CD 8（+）（CD 4和CD 8单阳性[SP]）胸腺细胞和T细胞的产生中具有关键功能。虽然Themis 1已被证明与接头蛋白LAT和Grb 2结合，但先前的研究对于Themis 1（-/-）小鼠的胸腺细胞是否表现出TCR介导的信号转导缺陷产生了相互矛盾的结果。在这项研究中，我们证明，在Themis 1的情况下，TCR介导的信号转导在CD 4 SP和CD 8 SP胸腺细胞中选择性受损，但在CD 4（+）CD 8（+）双阳性胸腺细胞中不受影响，尽管Themis 1在双阳性胸腺细胞中高表达。与Themis 1一样，Themis 2是Themis家族的相关成员，在B细胞和巨噬细胞中表达，含有两个保守的基于半胱氨酸的结构域、一个富含脯氨酸的区域和一个核定位信号。为了确定Themis 1和Themis 2是否可以在体内执行类似的功能，我们分析了用Themis 1或Themis 2转基因重建的Themis 1（-/-）小鼠中的T细胞发育和TCR介导的信号传导。值得注意的是，Themis 1和Themis 2在Themis 1（-/-）小鼠中表现出相同的恢复T细胞发育和TCR介导的信号传导的潜力。这两种蛋白质都被酪氨酸磷酸化，并在TCR接合后在Grb 2信号复合物内被募集到LAT。这些结果表明Themis 1和Themis 2蛋白的保守分子特征对于它们的生物学活性是重要的，并且预测Themis 1和Themis 2可能分别在T和B细胞中执行类似的功能。免疫学杂志，2012，189：1154-1161。
Themis1, a recently identified T cell protein, has a critical function in the generation of mature CD4(+)CD8(-) and CD4(-)CD8(+) (CD4 and CD8 single-positive [SP]) thymocytes and T cells. Although Themis1 has been shown to bind to the adaptor proteins LAT and Grb2, previous studies have yielded conflicting results regarding whether thymocytes from Themis1(-/-) mice exhibit TCR-mediated signaling defects. In this study, we demonstrate that, in the absence of Themis1, TCR-mediated signaling is selectively impaired in CD4 SP and CD8 SP thymocytes but is not affected in CD4(+)CD8(+) double-positive thymocytes despite high expression of Themis1 in double-positive thymocytes. Like Themis1, Themis2, a related member of the Themis family, which is expressed in B cells and macrophages, contains two conserved cysteine-based domains, a proline-rich region, and a nuclear localization signal. To determine whether Themis1 and Themis2 can perform similar functions in vivo, we analyzed T cell development and TCR-mediated signaling in Themis1(-/-) mice reconstituted with either Themis1 or Themis2 transgenes. Notably, Themis1 and Themis2 exhibited the same potential to restore T cell development and TCR-mediated signaling in Themis1(-/-) mice. Both proteins were tyrosine phosphorylated and were recruited within Grb2 signaling complexes to LAT following TCR engagement. These results suggest that conserved molecular features of the Themis1 and Themis2 proteins are important for their biological activity and predict that Themis1 and Themis2 may perform similar functions in T and B cells, respectively. The Journal of Immunology, 2012, 189: 1154-1161.