Comparison of thymocyte development in normal and invariant chain-deficient mice provides evidence that maturation-related changes in TCR and co-receptor levels play a critical role in cell fate.

Cells of invariant chain-deficient mice show a substantial decrease in cell surface MHC class II protein expression, as well as a change in the occupancy of the expressed class II molecules. Taking advantage of recent advances in phenotypic identification of transitional populations of developing thymocytes, the effects of these changes in MHC class II on positive and negative selection were reanalyzed. A marked (approximately 6-fold) reduction in CD4 single-positive mature cells was seen in H-2b mutant mice, yet there was little change in the number of CD4hiCD8intTCRint cells, a population containing the cells from which mature CD4+ cells derive. In normal mice expressing I-E and MMTV-encoded vSAG, V beta-specific negative selection occurred at a later point in the maturation pathway for cells showing greater expression of CD8 than CD4. In invariant chain-deficient mice, vSAG-mediated negative selection was diminished in general and what deletion still occurred was seen in more mature populations as compared to wild-type mice. Taken together, the decrease in MHC class II expression in invariant chain mutant mice and these alterations in the timing of thymocyte deletion provide strong support for an avidity model of negative selection. Perhaps more importantly, they emphasize the importance of the increasing TCR expression, the changing co-receptor levels and the movement from one antigen-presenting cell to another that accompany T cell maturation in determining the fate of developing thymocytes.