Enhanced positive selection of a transgenic TCR by a restriction element that does not permit negative selection.

Very little is known about the conformational properties of the MHC molecules that are able to signal positive selection of a given TCR. To try to understand these parameters and to determine whether these requirements are shared with interactions during negative selection and antigen recognition, we have studied selection and antigen recognition of a transgenic TCR (specific for lymphocytic choriomeningitis virus glycoprotein and H-2Db) in the context of two Db mutants, H-2bm13 and H-2bm14. The data showed that the transgenic TCR was not positively selected by the H-2bm14 haplotype but, interestingly, enhanced positive selection was seen in H-2bm13 mice. The transgenic TCR could not be negatively selected in H-2bm13 animals persistently infected with the virus (neonatal virus carrier mice), nor could the transgenic TCR be activated by H-2bm13 infected cells in vivo or in vitro. These experiments show that although a TCR may be selected by a mutant MHC molecule, the corresponding viral antigen cannot be recognized in context of the mutant MHC molecule, as judged by both negative selection and T cell reactivity in vivo and in vitro. The 'enhanced' positive selection occurring in the context of Dbm13 suggests that a different conformation of the MHC molecule is able to select the same TCR and also that various TCR-ligand avidities may permit positive selection.