Autonomous maturation of α/β T lineage cells in the absence of COOH-terminal Src kinase (Csk)
Autonomous maturation of α/β T lineage cells in the absence of COOH-terminal Src kinase (Csk)
复制标题
DOI：
10.1084/jem.193.7.815
复制
发表时间：
2001-04-02
影响因子：
15.3
通讯作者：
Tarakhovsky, A
中科院分区：
文献类型：
--
作者：
Schmedt, C;Tarakhovsky, A
未成熟胸腺细胞中羧基末端Src激酶（Csk）（Src家族蛋白酪氨酸激酶（PTK）的负调节因子）的缺失导致T细胞受体（TCR）β缺陷或重组激活基因（rag）-1缺陷小鼠中α/β T谱系细胞的发育。Csk作为Lck和Fyn活性的阻遏物的功能表明这些PTKs的激活是单独负责在Csk缺陷的T谱系细胞中观察到的表型。我们为这一观点提供了遗传学证据，因为在lck（-/-）fyn（-/-）csk缺陷小鼠中α/β T细胞发育受阻。目前尚不清楚在缺乏Csk的情况下Lck和Fyn的激活是否将α/β T细胞发育完全与表面表达受体的参与解偶联。我们表明，在小鼠表达α/β TCR的csk缺陷的胸腺细胞，阳性选择偏向于CD 4谱系，并不需要存在的主要组织相容性复合体（MHC）I类和II类。此外，将MHC I类限制性转基因TCR引入到缺乏csk的背景中导致在选择性和非选择性MHC背景中主要携带转基因TCR的CD 4 T细胞的发育。因此，TCR-MHC相互作用在不存在Csk的情况下对CD 4谱系的正选择和定型没有影响。然而，TCR介导的csk缺陷型TCR转基因细胞的阴性选择是正常的。这些数据表明，Csk介导的Src家族PTKs的调节在胸腺细胞的阳性和阴性选择中有不同的参与。
The deletion of COOH-terminal Src kinase (Csk), a negative regulator of Src family protein tyrosine kinases (PTKs), in immature thymocytes results in the development of alpha/beta T lineage cells in T cell receptor (TCR) beta -deficient or recombination activating gene (rag)-1-deficient mice. The function of Csk as a repressor of Lck and Fyn activity suggests activation of these PTKs is solely responsible for the phenotype observed in csk-deficient T lineage cells. We provide genetic evidence for this notion as alpha/beta T cell development is blocked in lck(-/-)fyn(-/-)csk-deficient mice. It remains unclear whether activation of Lck and Fyn in the absence of Csk uncouples alpha/beta T cell development entirely from engagement of surface-ex-pressed receptors. We show that in mice expressing the alpha/beta TCR on csk-deficient thymocytes, positive selection is biased towards the CD4 lineage and does not require the presence of major histocompatibility complex (MHC) class I and II. Furthermore, the introduction of an MHC class I-restricted transgenic TCR into a csk-deficient background results in the development of mainly CD4 T cells carrying the transgenic TCR both in selecting and nonselecting MHC background. Thus, TCR-MHC interactions have no impact on positive selection and commitment to the CD4 lineage in the absence of Csk. However, TCR-mediated negative selection of csk-deficient, TCR transgenic cells is normal. These data suggest a differential involvement of the Csk-mediated regulation of Src family PTKs in positive and negative selection of developing thymocytes.