INVOLVEMENT OF P21(RAS) DISTINGUISHES POSITIVE AND NEGATIVE SELECTION IN THYMOCYTES
INVOLVEMENT OF P21(RAS) DISTINGUISHES POSITIVE AND NEGATIVE SELECTION IN THYMOCYTES
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DOI：
10.1002/j.1460-2075.1995.tb07001.x
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发表时间：
1995-01-16
期刊：
影响因子：
11.4
通讯作者：
PERLMUTTER, RM
中科院分区：
文献类型：
--
作者：
SWAN, KA;ALBEROLAILA, J;PERLMUTTER, RM
ras家族的小分子量GTP结合蛋白与T细胞抗原受体（TCR）的信号转导有关。为了检测p21（ras）在控制胸腺细胞发育中的重要性，我们产生了表达显性阴性p21（ras）蛋白的小鼠在lck近端启动子控制下的T谱系细胞中的（H-rasN 17），来自lck-H-rasN 17小鼠的胸腺细胞响应于TCR刺激的增殖几乎被完全阻断，证实了p21（ras）在成熟CD 4（+）8（-）或CD 8（+）4（-）胸腺细胞中介导TCR衍生信号的重要性。相反，在表达显性阴性p21（ras）的小鼠的CD 4（+）8（+）胸腺细胞中，一些TCR衍生的信号未受损。对H-Y特异性TCR和lck-H-rasN 17双转基因小鼠胸腺细胞发育的分析表明，抗原特异性阴性选择在p21（H-rasN 17）存在下正常发生。H-rasN 17胸腺细胞在体内超抗原诱导的阴性选择也不受阻碍地进行，相反，H-Y小鼠胸腺细胞的阳性选择被p21（H-rasN 17）的存在严重损害。这些观察结果表明，积极和消极的选择，两个概念上对立的TCR刺激的结果，是生化区分。
Small molecular weight GTP binding proteins of the ras family have been implicated in signal transduction from the T cell antigen receptor (TCR), To test the importance of p21(ras) in the control of thymocyte development, we generated mice expressing a dominant-negative p21(ras) protein (H-rasN17) in T lineage cells under the control of the lck proximal promoter, Proliferation of thymocytes from lck-H-rasN17 mice in response to TCR stimulation was nearly completely blocked, confirming the importance of p21(ras) in mediating TCR-derived signals in mature CD4(+)8(-) or CD8(+)4(-) thymocytes. In contrast, some TCR-derived signals proceeded unimpaired in the CD4(+)8(+) thymocytes of mice expressing dominant-negative p21(ras). Analysis of thymocyte development in mice made doubly transgenic for the H-Y-specific TCR and lck-H-rasN17 demonstrated that antigen-specific negative selection occurs normally in the presence of p21(H-rasN17). Superantigen-induced negative selection in vivo also proceeded unhindered in H-rasN17 thymocytes, In contrast, positive selection of thymocytes in the H-Y mice was severely compromised by the presence of p21(H-rasN17). These observations demonstrate that positive and negative selection, two conceptually antithetical consequences of TCR stimulation, are biochemically distinguishable.