H-2(d) mice expressing both the influenza virus hemagglutinin (HA) as a transgene-encoded protein on pancreatic islet beta cells (InsHA), as well as the Clone 4 TCR specific for the dominant H-2K(d)-restricted HA epitope, can be protected from the development of spontaneous autoimmune diabetes by expression of the H-2(b) haplotype. Protection occurs due to the deletion of K(d)HA-specific CD8+ T cells. This was unexpected as neither the presence of the InsHA transgene nor H-2(b), individually, resulted in thymic deletion. Further analyses revealed that thymic deletion required both a hybrid MHC class II molecule, Ebeta(b) Ealpha(d), and the K(d) molecule presenting the HA epitope, which together synergize to effect deletion of CD4+CD8+ thymocytes. This surprising example of protection from autoimmunity that maps to a class II MHC molecule, yet effects an alteration in the CD8+ T cell repertoire, suggests that selective events in the thymus represent the integrated strength of signal delivered to each cell through recognition of a variety of different MHC-peptide ligands.