MHC Class I-Restricted Determinants on the Glutamic Acid Decarboxylase 65 Molecule Induce Spontaneous CTL Activity

• Published in: The Journal of immunology (1950) 2001-08, Vol.167 (3), p.1748-1757
• Main Authors: Quinn, Anthony, McInerney, Marcia F, Sercarz, Eli E
• Format: Article
• Language: English
• Subjects: Administration, Intranasal; Aging - immunology; Animals; Animals, Newborn; Animals, Suckling; CD8-Positive T-Lymphocytes - enzymology; CD8-Positive T-Lymphocytes - immunology; Cell Line; Cyclophosphamide - administration & dosage; Cytotoxicity Tests, Immunologic; Cytotoxicity, Immunologic - immunology; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - prevention & control; Epitopes, T-Lymphocyte - immunology; Female; Freund's Adjuvant - administration & dosage; Glutamate Decarboxylase - administration & dosage; Glutamate Decarboxylase - genetics; Glutamate Decarboxylase - immunology; H-2 Antigens - immunology; Immunodominant Epitopes - immunology; Injections, Intraperitoneal; Isoenzymes - administration & dosage; Isoenzymes - genetics; Isoenzymes - immunology; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Mice, SCID; Peptide Fragments - administration & dosage; Peptide Fragments - immunology; Rats; Spleen - cytology; Spleen - immunology; T-Lymphocyte Subsets - enzymology; T-Lymphocyte Subsets - immunology; T-Lymphocytes, Cytotoxic - enzymology; T-Lymphocytes, Cytotoxic - immunology; Transfection
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.167.3.1748

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.