Transgenic mice expressing a T cell receptor hetemdimer specific for a fragment of pigeon cytochrome c plus an MHC class II molecule (IE”) have been made. We find that H-2k afi transgenic mice have an overall increase in the number of T cells and express a lo-fold higher fraction of cytochrome c-reactive cells than H-2b mice. Surface staining of thymocytes indicates that in H-2b mice, T cell development is arrested at an intermediate stage of differentiation (CD4+ 8+, CD39. Analyses of mice carrying these T cell receptor genes and MHC class II IE, constructs indicate that this developmental block can be twemed in H-2b mice by IE expression on cortical epithelial cells of the thymus. These data suggest that a direct T cell receptor-MHC interaction occurs In the thymus in the absence of nominal antigen and results in the enhanced export of T cells, consistent with the concept of “positive selection.”