Thymic and postthymic regulation of diabetogenic CD8 T cell development in TCR transgenic nonobese diabetic (NOD) mice.
Natural development of diabetes in nonobese diabetic (NOD) mice requires both CD4 and CD8 T cells. Transgenic NOD mice carrying alphabeta TCR genes from a class I MHC (Kd)-restricted, pancreatic beta cell Ag-specific T cell clone develop diabetes significantly faster than nontransgenic NOD mice. In these TCR transgenic mice, a large fraction of T cells express both transgene derived and endogenous TCR beta chains. Only T cells expressing two TCR showed reactivity to the islet Ag. Development of diabetogenic T cells is inhibited in mice with no endogenous TCR expression due to the SCID mutation. These results demonstrate that the expression of two TCRs is necessary for the autoreactive diabetogenic T cells to escape thymic negative selection in the NOD mouse. Further analysis with MHC congenic NOD mice revealed that diabetes development in the class I MHC-restricted islet Ag-specific TCR transgenic mice is still dependent on the presence of the homozygosity of the NOD MHC class II I-Ag7.
Kanagawa
O
O
Center for Immunology and Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110, USA. kanagawa@pathbox.wustl.edu
Shimizu
J
J
Vaupel
B A
BA
D000483:Alleles; D000818:Animals; D001324:Autoantigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D005802:Genes, MHC Class II / Q000502:physiology; D019674:Genes, T-Cell Receptor beta; D007515:Islets of Langerhans / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis / Q000235:genetics*; D013950:Thymus Gland / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D019076:Transgenes / Q000276:immunology
D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D016693:Receptors, Antigen, T-Cell, alpha-beta