MHC class I-restricted determinants on the glutamic acid decarboxylase 65 molecule induce spontaneous CTL activity.
CD4(+) T cell responses to glutamic acid decarboxylase (GAD65) spontaneously arise in nonobese diabetic (NOD) mice before the onset of insulin-dependent diabetes mellitus (IDDM) and may be critical to the pathogenic process. However, since both CD4(+) and CD8(+) T cells are involved in autoimmune diabetes, we sought to determine whether GAD65-specific CD8(+) T cells were also present in prediabetic NOD mice and contribute to IDDM. To refine the analysis, putative K(d)-binding determinants that were proximal to previously described dominant Th determinants (206-220 and 524-543) were examined for their ability to elicit cytolytic activity in young NOD mice. Naive NOD spleen cells stimulated with GAD65 peptides 206-214 (p206) and 546-554 (p546) produced IFN-gamma and showed Ag-specific CTL responses against targets pulsed with homologous peptide. Conversely, several GAD peptides distal to the Th determinants, and control K(d)-binding peptides did not induce similar responses. Spontaneous CTL responses to p206 and p546 were mediated by CD8(+) T cells that are capable of lysing GAD65-expressing target cells, and p546-specific T cells transferred insulitis to NOD.scid mice. Young NOD mice pretreated with p206 and p546 showed reduced CTL responses to homologous peptides and a delay in the onset of IDDM. Thus, MHC class I-restricted responses to GAD65 may provide an inflammatory focus for the generation of islet-specific pathogenesis and beta cell destruction. This report reveals a potential therapeutic role for MHC class I-restricted peptides in treating autoimmune disease and revisits the notion that the CD4- and CD8-inducing determinants on some molecules may benefit from a proximal relationship.
Quinn
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A
Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, CA 92121, USA.
McInerney
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MF
Sercarz
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EE
D000281:Administration, Intranasal; D000375:Aging / Q000276:immunology; D000818:Animals; D000831:Animals, Newborn; D000833:Animals, Suckling; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology; D002460:Cell Line; D003520:Cyclophosphamide / Q000008:administration & dosage; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000517:prevention & control; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D005620:Freund's Adjuvant / Q000008:administration & dosage; D005968:Glutamate Decarboxylase / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D006183:H-2 Antigens / Q000276:immunology*; D016056:Immunodominant Epitopes / Q000276:immunology*; D007274:Injections, Intraperitoneal; D007527:Isoenzymes / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology; D051381:Rats; D013154:Spleen / Q000166:cytology / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000201:enzymology* / Q000276:immunology*; D014162:Transfection
D018984:Epitopes, T-Lymphocyte; D006183:H-2 Antigens; C024755:H-2K(K) antigen; D016056:Immunodominant Epitopes; D007527:Isoenzymes; D010446:Peptide Fragments; D003520:Cyclophosphamide; D005620:Freund's Adjuvant; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2