Coreceptor signal strength regulates positive selection but does not determine CD4/CD8 lineage choice in a physiologic in vivo model
Coreceptor signal strength regulates positive selection but does not determine CD4/CD8 lineage choice in a physiologic in vivo model
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DOI：
10.4049/jimmunol.177.10.6613
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发表时间：
2006-11-15
影响因子：
4.4
通讯作者：
Singer, Alfred
中科院分区：
文献类型：
--
作者：
Erman, Batu;Alag, Amala S.;Singer, Alfred
TCR信号驱动胸腺细胞发育，但这些信号的强度对胸腺中T细胞分化的影响（如果有的话）仍然存在争议。在这项研究中，我们评估了CD 8辅助受体信号强度对阳性选择和CD 4/CD 8谱系选择的影响，使用新的基因敲入小鼠，其中内源性CD 8 α基因已被重新设计为编码更强的信号转导细胞质尾的CD 4，与重新设计的CD 8 α基因被称为CD8.4。我们发现，更强的信号转导CD8.4辅助受体特异性地提高了CD 8依赖性阳性选择的效率，并定量地增加了MHC I类（MHC-I）特异性胸腺细胞分化为CD 8（+）T细胞的数量，即使是表达单一转基因TCR的胸腺细胞。然而，重要的是，更强的信号传导CD8.4辅助受体并不改变任何MHC-I特异性胸腺细胞的CD 8谱系选择，甚至是表达高亲和力F5转基因TCR的MHC-I特异性胸腺细胞。本研究在体内生理模型中记录了辅助受体信号强度改变阳性选择的TCR信号传导阈值，因此是CD 4：CD 8比率的主要决定因素，但它不影响CD 4/CD 8谱系选择。
TCR signals drive thymocyte development, but it remains controversial what impact, if any, the intensity of those signals have on T cell differentiation in the thymus. In this study, we assess the impact of CD8 coreceptor signal strength on positive selection and CD4/CD8 lineage choice using novel gene knockin mice in which the endogenous CD8 alpha gene has been re-engineered to encode the stronger signaling cytoplasmic tail of CD4, with the re-engineered CD8 alpha gene referred to as CD8.4. We found that stronger signaling CD8.4 coreceptors specifically improved the efficiency of CD8-dependent positive selection and quantitatively increased the number of MHC class I (MHC-I)-specific thymocytes signaled to differentiate into CD8(+) T cells, even for thymocytes expressing a single, transgenic TCR. Importantly, however, stronger signaling CD8.4 coreceptors did not alter the CD8 lineage choice of any MHC-I-specific thymocytes, even MHC-I-specific thymocytes expressing the high-affinity F5 transgenic TCR. This study documents in a physiologic in vivo model that coreceptor signal strength alters TCR-signaling thresholds for positive selection and so is a major determinant of the CD4:CD8 ratio, but it does not influence CD4/CD8 lineage choice.