Another view of the selective model of thymocyte selection.

Thymocyte commitment to the CD4 helper versus CD8 cytotoxic lineage has not been satisfactorily established. Two models have been elaborated: one based on instruction, the other on selection. Most previous results support the instructive model, but our comparison of thymocyte differentiation in MHC class II-, class I- and double-deficient mice provides data challenging it. There exists a significant population of CD4 single positive cells in class II-deficient animals that is intermediate in maturity between CD4+CD8+ and end-stage CD4+CD8- thymocytes and is selected on class I molecules; an equivalent CD8+CD4- population occurs in class I-deficient animals. We propose a selective model entailing two TCR-MHC molecule engagements: the first provokes random down-modulation of either CD4 or CD8 and a degree of differentiation; the second, requiring participation of the appropriate coreceptor, permits end-stage differentiation.