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In a Transgenic Model of Spontaneous Autoimmune Diabetes, Expression of a Protective Class II MHC Molecule Results in Thymic Deletion of Diabetogenic CD8⁺ T Cells¹

David J. Morgan^*, C. Thomas Nugent, Benjamin J. E. Raveney^* and Linda A. Sherman^2,

^* University of Bristol, School of Medical Sciences, Bristol, United Kingdom; Beckman Coulter, San Diego, CA 92121; and Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037

H-2^d mice expressing both the influenza virus hemagglutinin (HA) as a transgene-encoded protein on pancreatic islet 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^dHA-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, E^b E^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.

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