Regulation of pre-T cell receptor (pTα-TCRβ) gene expression during human thymic development

Abstract

In murine T cell development, early thymocytes that productively rearrange the T cell receptor (TCR) β locus are selected to continue maturation, before TCRα expression, by means of a pre-TCRα- (pTα-) TCRβ heterodimer (pre-TCR). The aim of this study was to identify equivalent stages in human thymocyte development. We show here that variable-diversity- joining region TCRβ rearrangement and the expression of full-length TCRβ transcripts have been initiated in some immature thymocytes at the TCRα/β- CD4+CD8- stage, and become common in a downstream subset of TCRα/β- CD4+CD8+ thymocytes that is highly enriched in large cycling cells. TCRβ chain expression was hardly detected in TCRα/β- CD4+CD8- thymocytes, whereas cytoplasmic TCRβ chain was found in virtually all TCRα/β- CD4+CD8+ blasts. In addition, a TCRβ complex distinct from the mature TCRα/β heterodimer was immunoprecipitated only from the latter subset. cDNA derived from TCRα/β- CD4+CD8+ blasts allowed us to identify and clone the gene encoding the human pTα chain, and to examine its expression at different stages of thymocyte development. Our results show that high pTα transcription occurs only in CD4+CD8+ and CD4+CD8+ TCRα/β- thymocytes, whereas it is weaker in earlier and later stages of development. Based on these results, we propose that the transition from TCRα/β- CD4+CD8- to TCRα/β- CD4+CD8+ thymocytes represents a critical developmental stage at which the successful expression of TCRβ promotes the clonal expansion and further maturation of human thymocytes, independent of TCRα.