In a Transgenic Model of Spontaneous Autoimmune Diabetes, Expression of a Protective Class II MHC Molecule Results in Thymic Deletion of Diabetogenic CD8+ T Cells

Abstract

H-2d mice expressing both the influenza virus hemagglutinin (HA) as a transgene-encoded protein on pancreatic islet β cells (InsHA), as well as the Clone 4 TCR specific for the dominant H-2Kd-restricted HA epitope, can be protected from the development of spontaneous autoimmune diabetes by expression of the H-2b haplotype. Protection occurs due to the deletion of KdHA-specific CD8+ T cells. This was unexpected as neither the presence of the InsHA transgene nor H-2b, individually, resulted in thymic deletion. Further analyses revealed that thymic deletion required both a hybrid MHC class II molecule, Eβb Eαd, and the Kd 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.