Regulation of NOD mouse autoimmune diabetes by T cells that recognize a TCR CDR3 peptide.
NOD mice spontaneously develop type I diabetes resulting from autoimmune destruction of their insulin-producing beta cells. Among the self-antigens targeted by NOD autoimmune T cells is a peptide, p277, from the sequence of the 60 kDa heat shock protein (hsp60). Common to the anti-p277 T cell populations of NOD mice is an idiotope, C9, that spans the CDR3 region of the C9 TCR. We now report: (i) that the C9 idiotope peptide can be presented directly to anti-C9 anti-idiotypic T cells by C9 T cells, (ii) that spontaneous anti-C9 anti-idiotypic T cell activity falls as disease progresses, but immunization can activate the anti-idiotypic T cells to regulate the autoimmune process, (iii) that the anti-idiotypic T cells secrete IFN-gamma, but appear to control the disease by down-regulating the IFN-gamma produced by the pathogenic population of anti-p277 T cells, (iv) that intrathymic administration of the C9 idiotope peptide at 1 week of age can accelerate the disease, and (v) that administering the p277 target peptide can up-regulate the anti-idiotypic T cells and arrest the disease process. Thus, the development of NOD diabetes can be regulated by a balance between anti-idiotypic and anti-target peptide autoimmunity, and anti-idiotypic regulation can lead to changes in the cytokine secretion of the autoimmune T cells involved in the disease process.
Elias
D
D
Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel.
Tikochinski
Y
Y
Frankel
G
G
Cohen
I R
IR
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D018834:Chaperonin 60; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000276:immunology*; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D006360:Heat-Shock Proteins / Q000276:immunology; D007130:Immunoglobulin Idiotypes / Q000276:immunology / Q000378:metabolism; D007272:Injections, Intralymphatic; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland; D015854:Up-Regulation / Q000276:immunology; D014612:Vaccines / Q000276:immunology
D018834:Chaperonin 60; D006360:Heat-Shock Proteins; D007130:Immunoglobulin Idiotypes; D010446:Peptide Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta; D014612:Vaccines; C095402:peptide 277, heat shock protein 60