Rudd Meghan L, Tua-Smith Alymarie, Straus David B
Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA 23298, USA.
Mol Cell Biol. 2006 Nov;26(21):7892-900. doi: 10.1128/MCB.00968-06. Epub 2006 Aug 21.
Thymocyte development is shaped by signals from the T-cell antigen receptor. The strength of receptor signaling determines developmental progression as well as deletion of self-reactive T cells. Receptor stimulation of the extracellular signal-regulated kinase (ERK) pathway plays an important regulatory role during thymocyte development. However, it is unclear how differences in receptor signaling are translated into distinctive activation of the ERK pathway. We have investigated the potential role of the Lck tyrosine kinase in regulating intracellular signaling during thymocyte development. While Lck is known to be critical for initial T-cell receptor signaling events, it may have an independent role in regulating intracellular signaling through the function of its SH3 domain. To determine whether such a regulatory mechanism functions during thymocyte development, we generated mice in which the normal lck allele is replaced with an lck SH3 domain mutant. Analysis of these mice revealed that both early thymocyte development and maturation of CD4(+) and CD8(+) lineages is impaired. Investigation of thymocyte responses to antigen receptor stimulation showed a significant reduction in proliferation and ERK pathway activation, although initial signaling events were intact. These findings indicate that Lck SH3 domain function may provide a means to independently couple receptor signaling to regulation of the ERK pathway during thymocyte development.
胸腺细胞的发育受来自T细胞抗原受体信号的影响。受体信号的强度决定了发育进程以及自身反应性T细胞的清除。细胞外信号调节激酶（ERK）途径的受体刺激在胸腺细胞发育过程中发挥重要的调节作用。然而，尚不清楚受体信号的差异是如何转化为ERK途径的独特激活的。我们研究了Lck酪氨酸激酶在胸腺细胞发育过程中调节细胞内信号传导的潜在作用。虽然已知Lck对初始T细胞受体信号事件至关重要，但它可能通过其SH3结构域的功能在调节细胞内信号传导方面具有独立作用。为了确定这种调节机制在胸腺细胞发育过程中是否起作用，我们生成了将正常lck等位基因替换为lck SH3结构域突变体的小鼠。对这些小鼠的分析表明，早期胸腺细胞发育以及CD4(+)和CD8(+)谱系的成熟均受损。对胸腺细胞对抗原受体刺激反应的研究表明，尽管初始信号事件完整，但增殖和ERK途径激活显著降低。这些发现表明，Lck SH3结构域功能可能提供一种在胸腺细胞发育过程中将受体信号与ERK途径调节独立偶联的方式。
