beta-selection is associated with the onset of CD8 beta chain expression on CD4(+)CD8 alpha alpha(+) pre-T cells during human intrathymic development

T-cell precursors that undergo productive rearrangements at the T-cell rece ptor (TCR) beta locus are selected for proliferation and further maturation , before TCR alpha expression, by signaling through a pre-TCR composed of t he TCR beta chain paired with a pre-TCR alpha (pT alpha) chain. Such a crit ical 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 D P compartment occurs in humans via a CD4(+) CD8(-) intermediate stage. Here we show that the CD4(+) CD8(-) to CD4(+) CD8(+) transition involves the se quential acquisition of the alpha and beta chains of CD8 at distinct matura tion stages. Our results indicate that CD8 alpha, but not CD8 beta, is expr essed in vivo in a minor subset of DP TCR alpha beta(-) thymocytes, referre d to as CD4(+) CD8 alpha alpha(+) pre-T cells, mostly composed of resting c ells lacking cytoplasmic TCR beta chain (TCR beta(ic)). In contrast, expres sion of CD8 alpha beta heterodimers was selectively found on DP TCR alpha b eta(-) thymocytes that express TCR beta(ic) and are enriched for cycling ce lls. Interestingly, CD4(+) CD8 alpha alpha(+) pre-T cells are shown to be f unctional intermediates between CD4(+) CD8(-) TCR beta(ic)(-) and CD4(+) CD 8 alpha beta(+) TCR beta(ic)(+) thymocytes. More importantly, evidence is p rovided that onset of CD8 beta and TCR beta(ic) expression are coincident d evelopmental events associated with acquisition of CD3 and pT alpha chain o n 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-T CR-mediated p-selection in human T-cell development, (C) 1999 by The Americ an Society of Hematology.