Stanford Genome Technology Center, Palo Alto, CA 94304, USA.
Proc Natl Acad Sci U S A. 2010 Jan 26;107(4):1518-23. doi: 10.1073/pnas.0913939107. Epub 2010 Jan 4.
Developing T cells face a series of cell fate choices in the thymus and in the periphery. The role of the individual T cell receptor (TCR) in determining decisions of cell fate remains unresolved. The stochastic/selection model postulates that the initial fate of the cell is independent of TCR specificity, with survival dependent on additional TCR/coreceptor "rescue" signals. The "instructive" model holds that cell fate is initiated by the interaction of the TCR with a cognate peptide-MHC complex. T cells are then segregated on the basis of TCR specificity with the aid of critical coreceptors and signal modulators [Chan S, Correia-Neves M, Benoist C, Mathis (1998) Immunol Rev 165: 195-207]. The former would predict a random representation of individual TCR across divergent T cell lineages whereas the latter would predict minimal overlap between divergent T cell subsets. To address this issue, we have used high-throughput sequencing to evaluate the TCR distribution among key T cell developmental and effector subsets from a single donor. We found numerous examples of individual subsets sharing identical TCR sequence, supporting a model of a stochastic process of cell fate determination coupled with dynamic patterns of clonal expansion of T cells bearing the same TCR sequence among both CD4(+) and CD8+ populations.
在胸腺和外周组织中，T 细胞的发育会面临一系列细胞命运的选择。个体 T 细胞受体（TCR）在决定细胞命运方面的作用仍未得到解决。随机/选择模型假设细胞的初始命运与 TCR 特异性无关，其存活取决于额外的 TCR/共受体“挽救”信号。“指令性”模型认为，细胞命运是由 TCR 与同源肽-MHC 复合物的相互作用启动的。然后，T 细胞基于 TCR 特异性在关键共受体和信号调节剂的辅助下进行分离[Chan S、Correia-Neves M、Benoist C、Mathis（1998）免疫评论 165:195-207]。前者将预测单个 TCR 在不同的 T 细胞谱系中随机出现，而后者则预测不同的 T 细胞亚群之间很少有重叠。为了解决这个问题，我们使用高通量测序来评估单个供体中关键 T 细胞发育和效应亚群的 TCR 分布。我们发现许多例子表明，不同的 T 细胞亚群共享相同的 TCR 序列，这支持了一种随机的细胞命运决定模型，该模型与 TCR 序列相同的 T 细胞在 CD4(+)和 CD8+群体中克隆性扩张的动态模式相耦合。
