MHC Recognition in Thymic Development: Distinct, Parallel Pathways for Survival and Lineage Commitment1

The molecular events triggered by MHC recognition and how they lead to the emergence of mature CD4 and CD8 lineage thymocytes are not yet understood. To address these questions, we have examined what signals are necessary to drive the development of CD8 lineage thymocytes in TCRα− mice in which TCR/MHC engagement cannot occur. We find that the combination of constitutive Notch activity and constitutive Bcl-2 expression are necessary and sufficient to allow the appearance of mature CD8 lineage thymocytes in TCRα− mice. In addition, Notch activity alone in TCRα− mice can induce the up-regulation of HES1, suggesting that thymocytes are competent to respond to Notch signaling in the absence of MHC recognition. These data indicate that survival and lineage commitment represent distinct, parallel pathways that occur as a consequence of MHC recognition, both of which are necessary for the development of mature CD8 lineage T cells.

由主要组织相容性复合体（MHC）识别所触发的分子事件以及它们如何导致成熟的CD4和CD8谱系胸腺细胞的出现尚未被了解。为了解决这些问题，我们研究了在T细胞受体α链缺失（TCRα−）小鼠中驱动CD8谱系胸腺细胞发育需要哪些信号，在这种小鼠中T细胞受体/主要组织相容性复合体（TCR/MHC）的结合无法发生。我们发现组成性Notch活性和组成性Bcl - 2表达的组合对于允许TCRα−小鼠中成熟CD8谱系胸腺细胞的出现是必要且充分的。此外，在TCRα−小鼠中单独的Notch活性能够诱导HES1的上调，这表明在没有MHC识别的情况下胸腺细胞能够对Notch信号作出反应。这些数据表明存活和谱系定型代表了因MHC识别而产生的不同的平行途径，这两者对于成熟CD8谱系T细胞的发育都是必需的。