THE PROTEIN-TYROSINE KINASE P56(LCK) REGULATES TCR EXPRESSION AND T-CELL SELECTION
THE PROTEIN-TYROSINE KINASE P56(LCK) REGULATES TCR EXPRESSION AND T-CELL SELECTION
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DOI：
10.1093/intimm/7.4.617
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发表时间：
1995-04-01
影响因子：
4.4
通讯作者：
TEH, HS
中科院分区：
文献类型：
--
作者：
ERICSSON, PO;TEH, HS
通过将TCR转基因小鼠与表达lck F505的转基因小鼠交配，评价了蛋白酪氨酸激酶(PTK)p56(Lck)在T细胞发育中的作用。TCR转基因小鼠表达D-b(H-Y)提呈的雄性抗原特异性受体(H-Y TCR)或I-E(K)Ⅱ类MHC分子提呈的鸽子细胞色素c多肽受体(和TCR)。在正常小鼠和TCR转基因小鼠未成熟的CD4(+)CD8(+)胸腺细胞中，转lck F505基因的小鼠TCR表达降低。与激活的p56(Lck)导致TCR表达降低的结论一致，PTK抑制剂Herbimycin A能够使TCR/lck F505双转基因小鼠的CD4(+)CD8(+)胸腺细胞TCR表达恢复到正常水平。然而，尽管TCR表达较低，但在H-Y TCR/lck F505双转基因小鼠的CD4(+)CD8(+)胸腺细胞中，钙动员仅适度减少。此外，在H-Y TCR/lck F505双转基因雄性小鼠中，尽管TCR水平较低，但表达H-Y TCR的CD4(+)CD8(+)胸腺细胞仍有效地发生了负选择。相比之下，对H-Y TCR/lck F505和TCR/lck F505双转基因小鼠的分析表明，转基因后这些小鼠的阳性选择减少了4-5倍。在双转基因lck F505小鼠中，阳性选择的细胞比例较小，表达正常水平的TCR，但表达适当的CD4或CD8共同受体分子的水平较高。这些结果表明，胸腺细胞的正向选择受p56lck酶活性的调节。
The role of the protein tyrosine kinase (PTK), p56(lck), in T cell development was evaluated by mating TCR transgenic mice with transgenic mice that expressed lckF505, a constitutively activated form of p56(lck) which is under the control of the lck proximal promoter element. The TCR transgenic mice expressed either a receptor specific for the male antigen presented by D-b (H-Y TCR) or a receptor specific for pigeon cytochrome c peptide presented by I-E(k) class II MHC molecules (AND TCR). The lckF505 transgene caused lower TCR expression in immature CD4(+)CD8(+) thymocytes from normal and TCR transgenic mice. Consistent with the conclusion that activated p56(lck) causes lower TCR expression, the PTK inhibitor, herbimycin A, was able to restore TCR expression to normal levels in CD4(+)CD8(+) thymocytes from TCR/lckF505 doubly transgenic mice. However, despite lower TCR expression, calcium mobilization was only moderately reduced in CD4(+)CD8(+) thymocytes from H-Y TCR/lckF505 doubly transgenic mice. Furthermore, negative selection of CD4(+)CD8(+) thymocytes expressing the H-Y TCR occurred efficiently in H-Y TCR/lckF505 doubly transgenic male mice despite lower TCR levels. By contrast, analysis of H-Y TCR/lckF505 and AND TCR/lckF505 doubly transgenic mice showed that positive selection in these mice was reduced by 4- to 5-fold by thelckF505 transgene. The smaller proportion of cells that were positively selected in doubly transgenic lckF505 mice expressed normal levels of TCR but higher levels of the appropriate CD4 or CD8 co-receptor molecule. These results indicate that the positive selection of thymocytes is regulated by the enzymatic activity of p56lck.