REGULATION OF PRE-T CELL-RECEPTOR (PT-ALPHA-TCR-BETA) GENE-EXPRESSIONDURING HUMAN THYMIC DEVELOPMENT

In murine T cell development, early thymocytes that productively rearr ange the T cell receptor (TCR)beta locus are selected to continue matu ration, before TCR alpha expression, by means of a pre-TCR alpha- (pT alpha-) TCR beta heterodimer (pre-TCR). The aim of this study was to i dentify equivalent stages in human thymocyte development. We show here that variable-diversity-joining region TCR beta rearrangement and the expression of full-length TCR beta transcripts have been initiated in some immature thymocytes at the TCR alpha/beta(-) CD4(+)CD8(+) stage, and become common in a downstream subset of TCR alpha/beta(-) CD4(+)C D8(+) thymocytes that is highly enriched in large cycling cells. TCRP chain expression was hardly detected in TCR alpha/beta(-) CD4(+)CD8(-) thymocytes, whereas cytoplasmic TCR beta chain was found in virtually all TCR alpha/beta(-) CD4(+)CD8(+) blasts. In addition, a TCR beta co mplex distinct from the mature TCR alpha/beta heterodimer was immunopr ecipitated only from the latter subset. cDNA derived from TCR alpha/be ta(-) CD4(+)CD8(+) blasts allowed us to identify and clone the gene en coding the human pT alpha chain, and to examine its expression at diff erent stages of thymocyte development. Our results show that high pT a lpha transcription occurs only in CD4(+)CD8(-) and CD4(+)CD8(+) TCR al pha/beta(-) thymocytes, whereas it is weaker in earlier and later stag es of development. Based on these results, we propose that the transit ion from TCR alpha/beta(-) CD4(+)CD8(-) to TCR alpha/beta(-) CD4(+)CD8 (+) thymocytes represents a critical developmental stage at which the successful expression of TCR beta promotes the clonal expansion and fu rther maturation of human thymocytes, independent of TCR alpha.