Selective regulation of TCR signaling pathways by the CD45 protein tyrosine phosphatase during thymocyte development.
Selective regulation of TCR signaling pathways by the CD45 protein tyrosine phosphatase during thymocyte development.
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DOI：
10.4049/jimmunol.181.9.6082
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发表时间：
2008-11-01
期刊：
影响因子：
--
通讯作者：
Leitenberg D
中科院分区：
文献类型：
--
作者：
Falahati R;Leitenberg D
在CD45缺陷的动物中，胸腺细胞的阳性选择存在严重缺陷，导致成熟T细胞的缺失和胸腺细胞在发育的双阳性阶段积累。然而，导致成熟单个阳性T细胞发育受阻的信号缺陷(S)还没有得到很好的描述。以前的研究发现，CD45缺陷细胞系和胸腺细胞在抗CD3刺激后早期信号转导事件显著减少。然而，也有一些情况下，T细胞激活和TCR信号事件可以在没有CD45的情况下被诱导。例如，与CD3单独交联相比，CD3和CD4同时抗体交联后，CD45非依赖的TCR信号可以恢复。这些数据表明，CD45可能根据信号的性质和/或细胞的分化状态而不同地调节TCR信号事件。在目前的研究中，我们评估了CD45在多肽生理刺激后调节初级胸腺细胞激活中的作用。与CD3介导的刺激不同，CD45缺陷胸腺细胞的肽刺激可以诱导较少但容易检测到的TCR介导的信号事件，如TCR相关的Zeta、ZAP70、LAT和Akt的磷酸化，并增加细胞内钙离子浓度。相反，在缺乏CD45的情况下，ERK的磷酸化受到更严重的影响，而ERK的磷酸化是正选择所必需的。这些数据表明CD45在调节T细胞激活的不同方面具有选择性作用。
In CD45 deficient animals there is a severe defect in thymocyte positive selection, resulting in an absence of mature T cells and the accumulation of thymocytes at the double positive stage of development. However, the signaling defect(s) responsible for the block in development of mature single positive T cells are not well characterized. Previous studies have found that early signal transduction events in CD45 deficient cell lines and thymocytes are markedly diminished following stimulation with anti-CD3. Nevertheless, there are also situations in which T cell activation and TCR signaling events can be induced in the absence of CD45. For example, CD45 independent TCR signaling can be recovered upon simultaneous antibody cross-linking of CD3 and CD4 compared to cross-linking of CD3 alone. These data suggest that CD45 may differentially regulate TCR signaling events depending on the nature of the signal and/or on the differentiation state of the cell. In the current study we have assessed the role of CD45 in regulating primary thymocyte activation following physiologic stimulation with peptide. Unlike CD3 mediated stimulation, peptide stimulation of CD45 deficient thymocytes induces diminished, but readily detectable TCR mediated signaling events such as phosphorylation of TCR-associated zeta, ZAP70, LAT, and Akt, and increased intracellular calcium concentration. In contrast, phosphorylation of ERK, which is essential for positive selection, is more severely affected in the absence of CD45. These data suggest that CD45 has a selective role in regulating different aspects of T cell activation.
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