Unexpectedly complex regulation of CD4/CD8 coreceptor expression supports a revised model for CD4(+)CD8(+) thymocyte differentiation

CD4(+)CD8(+)TCR(lo) thymocytes are the precursors of CD4(+) and CD8(+) mature T cells, whose receptors show specific recognition of peptide-MHC class II and MHC class I complexes, respectively. How T cells emerge from the intrathymic differentiation process with selective expression of either CD8 molecule or CD4 molecule coordinated with the MHC class specificity of the TCR has been the subject of intense examination. Many previous studies of this question have been based on the assumption that extinction of CD4 or CD8 expression by the precursor thymocytes was a steady, uninterrupted process. Here we show that this is an incorrect assumption, with CD4 and CD8 expression undergoing an unexpectedly complex series of expression changes involving down-modulation, kinetically asymmetric up-regulation, and then selective loss. Based on these data, we propose a model for the differentiation pathway of alpha beta TCR thymocytes that explains previous, apparently contradictory findings and establishes useful parameters for future studies at the cellular and gene level.