β-selection is associated with the onset of CD8β chain expression on CD4+CD8αα+ pre-T cells during human intrathymic development

T-cell precursors that undergo productive rearrangements at the T-cell receptor (TCR) beta locus are selected for proliferation and further maturation, before TCR alpha expression, by signaling through a pre-TCR composed of the TCR beta chain paired with a pre-TCR alpha (pT alpha) chain. Such a critical developmental checkpoint, known as p-selection, results in progression from CD4(-) CD8(-) double negative (DN) to CD4(+) CD8(+) double positive (DP) TCR alpha beta(-) thymocytes. In contrast to mice, progression to the DP compartment occurs in humans via a CD4(+) CD8(-) intermediate stage. Here we show that the CD4(+) CD8(-) to CD4(+) CD8(+) transition involves the sequential acquisition of the alpha and beta chains of CD8 at distinct maturation stages. Our results indicate that CD8 alpha, but not CD8 beta, is expressed in vivo in a minor subset of DP TCR alpha beta(-) thymocytes, referred to as CD4(+) CD8 alpha alpha(+) pre-T cells, mostly composed of resting cells lacking cytoplasmic TCR beta chain (TCR beta(ic)). In contrast, expression of CD8 alpha beta heterodimers was selectively found on DP TCR alpha beta(-) thymocytes that express TCR beta(ic) and are enriched for cycling cells. Interestingly, CD4(+) CD8 alpha alpha(+) pre-T cells are shown to be functional intermediates between CD4(+) CD8(-) TCR beta(ic)(-) and CD4(+) CD8 alpha beta(+) TCR beta(ic)(+) thymocytes. More importantly, evidence is provided that onset of CD8 beta and TCR beta(ic) expression are coincident developmental events associated with acquisition of CD3 and pT alpha chain on the cell surface. Therefore, we propose that the CD4+ CD8 alpha alpha(+) to CD4(+) CD8 alpha beta(+) transition marks the key control point of pre-TCR-mediated p-selection in human T-cell development, (C) 1999 by The American Society of Hematology.