One of the major mechanisms for establishing self-tolerance is the clonal deletion ofself-reactive T cells during their development in the thymus. Using a TCR transgenic mousemodel, we have established a quantitativeex vivoassay for examining the sensitivity andspecificity of negative selection. Thymic organ cultures established from mice of varyingMHC haplotypes were incubated with antigen, and the efficiency of clonal deletionassessed. We show here that clonal deletion of CD4+8+thymocytes is sensitive to both thegene dosage and the allelic variation of MHC class II molecules expressed on thymicantigen-presenting cells. We also find that when epithelial cells in the thymic cortex are theonly antigen-presenting cells expressing the appropriate MHC class II molecules, negativeselection of CD4+8+cells is as efficient as when antigen is presented on all thymicantigen-presenting cells. These studies demonstrate that the induction of self-tolerance viaclonal deletion in the thymus is a function not only of antigen concentration, but also ofMHC class II cell-surface density. In addition, together with the reports of others, theseresults confirm that cortical epithelial cells can mediate negative selection, and demonstratethat they do so in the intact thymic microenvironment.
展开▼
