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.
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.
Morgan
David J
DJ
University of Bristol, School of Medical Sciences, Bristol, United Kingdom.
Nugent
C Thomas
CT
Raveney
Benjamin J E
BJ
Sherman
Linda A
LA
D000818:Animals; D000831:Animals, Newborn; D015704:CD4 Antigens / Q000096:biosynthesis / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D017637:Clonal Deletion / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D004195:Disease Models, Animal; D006183:H-2 Antigens / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000502:physiology; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D064532:Histocompatibility Antigen H-2D; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D007328:Insulin / Q000235:genetics / Q000276:immunology; D007515:Islets of Langerhans / Q000276:immunology / Q000378:metabolism / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000276:immunology; D051381:Rats; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis; D013950:Thymus Gland / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*
D015704:CD4 Antigens; D006183:H-2 Antigens; C024755:H-2K(K) antigen; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D064532:Histocompatibility Antigen H-2D; D000949:Histocompatibility Antigens Class II; D007328:Insulin; D011948:Receptors, Antigen, T-Cell