EVIDENCE FOR A SINGLE-NICHE MODEL OF POSITIVE SELECTION

Thymocyte maturation depends on interactions with thymic stromal eleme nts expressing major histocompatibility complex (MHC) molecules. Mutan t mouse strains lacking MHC class I (beta(2)-microglobulin-null) or cl ass II (A(beta)-null) expression fail to generate normal CD8 or CD4 T- cell populations and provide model systems for reconstitution experime nts. We have constructed in vitro chimeras between normal and MHC-defi cient thymi to evaluate the efficiency of positive selection. Unexpect edly, the generation of mature single-positive thymocytes was proporti onal to the fraction of wild-type (i.e., MHC-expressing) stroma over a wide range of chimerism. Similar results were obtained for the develo pment of T-cell receptor-transgenic thymocytes in graded chimeras expr essing selecting and nonselecting MHC alleles. These findings are best explained by hypothesizing that positive selection involves a rate-li miting step at which each thymocyte can interact with only one stromal cell niche.