Chan S H, Waltzinger C, Baron A, Benoist C, Mathis D
Laboratoire de Génétique Moléculaire des Eucaryotes du CNRS, Unité 184 de Biologie Moléculaire et de Génie Génétique de l'INSERM, Faculté de Médecine, Strasbourg.
EMBO J. 1994 Oct 3;13(19):4482-9. doi: 10.1002/j.1460-2075.1994.tb06770.x.
Recent experiments have re-awakened interest in a stochastic/selective model of positive selection of T lymphocytes. A revised version of the model has been proposed whereby commitment of double-positive thymocytes to either the CD4 or CD8 lineage requires two engagements with MHC molecules: the first, initiating the differentiation program, signals down-regulation of one or the other coreceptor, regardless of the T cell receptor's specificity for MHC class I or II molecules; the second, leading to terminal differentiation, screens the choice of coreceptor by permitting only those cells with matched receptors and coreceptors to proceed. Here we explore the role of coreceptors in the two stages of positive selection by manipulating CD8 expression in MHC class II-deficient mice, crossing them with either CD8-negative animals or animals carrying combinations of CD8 alpha and CD8 beta transgenes. We find that coreceptors are required at both stages of positive selection and that artificial expression of the down-modulated CD8 molecule can quite efficiently rescue cells that have made a 'mistake' in their choice of coreceptor. We also establish that commitment to the CD4 pathway and to the helper phenotype can be linked.
最近的实验重新唤起了人们对T淋巴细胞阳性选择的随机/选择模型的兴趣。有人提出了该模型的一个修订版本，即双阳性胸腺细胞向CD4或CD8谱系的定向分化需要与MHC分子进行两次结合：第一次结合启动分化程序，信号传导导致其中一个共受体下调，而不考虑T细胞受体对MHC I类或II类分子的特异性；第二次结合导致终末分化，通过只允许那些受体和共受体匹配的细胞继续分化来筛选共受体的选择。在这里，我们通过在MHC II类缺陷小鼠中操纵CD8表达，将它们与CD8阴性动物或携带CD8α和CD8β转基因组合的动物杂交，来探讨共受体在阳性选择两个阶段中的作用。我们发现，共受体在阳性选择的两个阶段都是必需的，并且下调的CD8分子的人工表达可以相当有效地挽救那些在共受体选择上“犯错”的细胞。我们还确定了向CD4途径的定向分化与辅助性表型之间可以建立联系。
