Hesslein David G T, Takaki Rayna, Hermiston Michelle L, Weiss Arthur, Lanier Lewis L
Department of Microbiology and Immunology and Cancer Research Institute, University of California, San Francisco, CA 94143, USA.
Proc Natl Acad Sci U S A. 2006 May 2;103(18):7012-7. doi: 10.1073/pnas.0601851103. Epub 2006 Apr 20.
CD45, a protein tyrosine phosphatase that regulates Src family kinases, is important for regulating T cell and B cell receptor signaling; however, little is known about how CD45 regulates immunoreceptor tyrosine-based activation motif (ITAM)-dependent natural killer (NK) cell receptor signaling and the resulting effector functions. NK cells from CD45-deficient mice are relatively competent for ITAM receptor-induced cell-mediated cytotoxicity, yet completely deficient for cytokine secretion after stimulation with ligands to or antibodies against NK1.1, CD16, Ly49H, Ly49D, and NKG2D. This deficiency in cytokine/chemokine production occurs at the level of mRNA expression. After receptor engagement, extracellular signal-regulated kinase and c-Jun N-terminal kinase activation was markedly perturbed, whereas p38 activation was not substantially affected. The pattern and amounts of basal tyrosine phosphorylation were altered in freshly isolated NK cells and were surprisingly and markedly increased in IL-2-expanded NK cells from CD45-/- mice. These findings indicate that CD45-dependent regulation of ITAM-dependent signaling pathways is essential for NK cell-mediated cytokine production but not cytolytic activity.
CD45是一种调节Src家族激酶的蛋白酪氨酸磷酸酶，对调节T细胞和B细胞受体信号传导很重要；然而，关于CD45如何调节基于免疫受体酪氨酸的激活基序（ITAM）依赖性自然杀伤（NK）细胞受体信号传导及由此产生的效应功能，人们了解甚少。来自CD45缺陷小鼠的NK细胞对ITAM受体诱导的细胞介导的细胞毒性具有相对正常的能力，但在用针对NK1.1、CD16、Ly49H、Ly49D和NKG2D的配体或抗体刺激后，其细胞因子分泌则完全缺陷。细胞因子/趋化因子产生的这种缺陷发生在mRNA表达水平。受体结合后，细胞外信号调节激酶和c-Jun氨基末端激酶的激活明显受到干扰，而p38的激活则没有受到实质性影响。基础酪氨酸磷酸化的模式和量在新鲜分离的NK细胞中发生了改变，并且在来自CD45-/-小鼠的IL-2扩增的NK细胞中令人惊讶地显著增加。这些发现表明，CD45对ITAM依赖性信号通路的调节对于NK细胞介导的细胞因子产生至关重要，但对细胞溶解活性并非如此。
