Allelic exclusion and differentiation by protein kinase C-mediated signalsin immature thymocytes

Pre-T cell receptor (preTCR)-derived signals mediate the transition of thym ocytes from the CD4(-) CD8(-) double-negative (DN) to CD4(+) CD8(+) double- positive stage of T lymphocyte development. This progression, termed beta - selection, is limited to thymocytes that have generated a functional TCR-be ta chain able to associate with pT alpha to form the preTCR complex. Format ion of the preTCR complex not only induces differentiation, survival, and p roliferation of DN thymocytes; it also inhibits further TCR-beta gene rearr angement through an ill-defined process known as allelic exclusion. The sig naling pathways controlling this critical developmental checkpoint have not been characterized. Here we demonstrate that formation of the preTCR compl ex leads to the activation of protein kinase C (PKC), and that activation o f PKC is necessary for the differentiation and expansion of DN thymocytes. Importantly, we also show that allelic exclusion at the TCR-beta gene loci is enforced by PKC-mediated signals. These results define PKC as a central mediator of both differentiation and allelic exclusion during thymocyte dev elopment.