Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Animals, Newborn
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CD4 Antigens / biosynthesis
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CD4 Antigens / physiology
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CD8-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / metabolism
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CD8-Positive T-Lymphocytes / pathology*
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Cell Differentiation / genetics
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Cell Differentiation / immunology
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Clonal Deletion / genetics*
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Diabetes Mellitus, Type 1 / genetics*
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Diabetes Mellitus, Type 1 / immunology*
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Diabetes Mellitus, Type 1 / pathology
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Diabetes Mellitus, Type 1 / prevention & control
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Disease Models, Animal
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H-2 Antigens / biosynthesis
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H-2 Antigens / genetics
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H-2 Antigens / immunology
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H-2 Antigens / physiology
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Hemagglutinin Glycoproteins, Influenza Virus / biosynthesis
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Hemagglutinin Glycoproteins, Influenza Virus / genetics
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Hemagglutinin Glycoproteins, Influenza Virus / immunology
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Histocompatibility Antigen H-2D
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Histocompatibility Antigens Class II / biosynthesis*
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Histocompatibility Antigens Class II / genetics
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Histocompatibility Antigens Class II / physiology
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Insulin / genetics
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Insulin / immunology
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Islets of Langerhans / immunology
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Islets of Langerhans / metabolism
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Islets of Langerhans / virology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Promoter Regions, Genetic / immunology
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Rats
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Receptors, Antigen, T-Cell / biosynthesis
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Thymus Gland / immunology*
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Thymus Gland / metabolism
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Thymus Gland / pathology*
Substances
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CD4 Antigens
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H-2 Antigens
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H-2K(K) antigen
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Hemagglutinin Glycoproteins, Influenza Virus
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Histocompatibility Antigen H-2D
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Histocompatibility Antigens Class II
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Insulin
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Receptors, Antigen, T-Cell