Thymic positive selection and peripheral activation of islet antigen-specific T cells: separation of two diabetogenic steps by an I-A(g7) class II MHC beta-chain mutant.
The diabetes-susceptible class II MHC genes (in human and mouse) share unique nonaspartic acid residues at position 57 of the class II beta-chain. Transgenic expression of a mutant I-A(g7), substituting histidine and serine at position 56 and 57 of beta-chain with proline and aspartic acid (I-A(g7)PD), respectively, inhibits diabetes development in the nonobese diabetic mouse model. Here, we demonstrate that immature thymocytes expressing a diabetogenic islet Ag-specific transgenic TCR are positively selected by I-A(g7)PD class II MHC to give rise to mature CD4+ T cells. However, splenic APCs expressing the same I-A(g7)PD fail to present pancreatic islet Ag to mature T cells bearing this diabetogenic TCR. These results indicate that nonaspartic acid residues at position 57 of class II MHC beta-chain is important for diabetogenic CD4+ T cell activation in the periphery but is not essential for the formation of a diabetogenic T cell repertoire in the thymus.
Kanagawa
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O
Department of Pathology, Center for Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. kanagawa@pathology.wustl.edu
Vaupel
B A
BA
Xu
G
G
Unanue
E R
ER
Katz
J D
JD
D019943:Amino Acid Substitution; D000818:Animals; D017951:Antigen Presentation; D001327:Autoimmune Diseases / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D017637:Clonal Deletion; D003062:Codon / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000235:genetics* / Q000276:immunology; D007515:Islets of Langerhans / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D017354:Point Mutation; D011401:Promoter Regions, Genetic; D011828:Radiation Chimera; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D013047:Specific Pathogen-Free Organisms; D013154:Spleen / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000473:pathology; D013950:Thymus Gland / Q000276:immunology* / Q000473:pathology
D003062:Codon; D018076:DNA, Complementary; D000949:Histocompatibility Antigens Class II; C024138:I-E-antigen; D011948:Receptors, Antigen, T-Cell