Deletion of CD4 and CD8 coreceptors permits generation of αβT cells that recognize antigens independently of the MHC

The thymus generates major histocompatibility complex (MHC)-restricted alpha beta T cells that only recognize antigenic ligands in association with MHC or MHC-like molecules. We hypothesized that MHC specificity might be imposed on a broader alpha beta TCR repertoire during thymic selection by CD4 and CD8 coreceptors; that bind and effectively sequester the tyrosine kinase Lck, thereby preventing T cell receptor (TCR) signaling by non-MHC ligands that do not engage either coreceptor. This hypothesis predicts that, in coreceptor-deficient mice, alpha beta thymocytes would be signaled by non-MHC ligands to differentiate into alpha beta T cells lacking MHC specificity. We now report that MHC-independent alpha beta T cells were indeed generated in mice deficient in both coreceptors as well as MHC ("quad-deficient" mice) and that such mice contained a diverse alpha beta T cell repertoire whose MHC independence was confirmed at the clonal level. We conclude that CD4 and CD8 coreceptors impose MHC specificity on a broader alpha beta TCR repertoire during thymic selection by preventing thymocytes from being signaled by non-MHC ligands.