Howard Hughes Medical Institute, Rosalind Russell Medical Research Center for Arthritis, Department of Medicine, Department of Microbiology and Immunology, University of California-San Francisco, California, USA.
Nat Immunol. 2010 Dec;11(12):1085-92. doi: 10.1038/ni.1955. Epub 2010 Oct 31.
To investigate the role of the kinase Zap70 in T cells, we generated mice expressing a Zap70 mutant whose catalytic activity can be selectively blocked by a small-molecule inhibitor. We found that conventional naive, effector and memory T cells were dependent on the kinase activity of Zap70 for their activation, which demonstrated a nonredundant role for Zap70 in signals induced by the T cell antigen receptor (TCR). In contrast, the catalytic activity of Zap70 was not required for activation of the GTPase Rap1 and inside-out signals that promote integrin adhesion. This Zap70 kinase-independent pathway was sufficient for the suppressive activity of regulatory T cells (T(reg) cells), which was unperturbed by inhibition of the catalytic activity of Zap70. Our results indicate Zap70 is a likely therapeutic target.
为了研究激酶 Zap70 在 T 细胞中的作用，我们构建了一种表达 Zap70 突变体的小鼠，这种突变体的催化活性可以被一种小分子抑制剂特异性阻断。我们发现，常规的幼稚、效应和记忆 T 细胞依赖 Zap70 的激酶活性来激活，这表明 Zap70 在 T 细胞抗原受体（TCR）诱导的信号中具有非冗余的作用。相比之下，Zap70 的催化活性对于激活 GTPase Rap1 和促进整合素黏附的内向外信号并不必需。这种 Zap70 激酶非依赖性途径足以激活调节性 T 细胞（Treg 细胞）的抑制活性，而 Zap70 催化活性的抑制并不影响其抑制活性。我们的研究结果表明，Zap70 可能是一个有希望的治疗靶点。
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