title: Regulatory and effector CD4 T cells in nonobese diabetic mice recognize overlapping determinants on glutamic acid decarboxylase and use distinct V beta genes.
abstract: The 524--543 region of glutamic acid decarboxylase (GAD65), GAD65(524--543), is one of the first fragments of this islet Ag to induce proliferative T cell responses in the nonobese diabetic (NOD) mouse model of spontaneous autoimmune diabetes. Furthermore, NOD mice given tolerogenic doses of GAD65(524--543) are protected from spontaneous and cyclophosphamide-induced diabetes. In this study, we report that there are at least two I-A(g7)-restricted determinants present in the GAD65(524--543) sequence, each capable of recruiting unique T cell repertoires characterized by distinct TCR V beta gene use. CD4(+) T cells arise spontaneously in young NOD mice to an apparently dominant determinant found within the GAD65 peptide 530--543 (p530); however, T cells to the overlapping determinant 524-538 (p524) dominate the response only after immunization with GAD65(524--543). All p530-responsive T cells used the V beta 4 gene, whereas the V beta 12 gene is preferentially used to encode the TCR of p524-responsive T cell populations. T cell clones and hybridomas from both of these T cell groups were responsive to APC pulsed with GAD65(524--543) or whole rGAD65. p524-reactive cells appeared to be regulatory upon adoptive transfer into young NOD mice and could inhibit insulin-dependent diabetes mellitus development, although they were unable to produce IL-4, IL-10, or TGF beta upon antigenic challenge. Furthermore, we found that i.p. injection with p524/IFA was very effective in providing protection from cyclophosphamide-induced insulin-dependent diabetes mellitus. These data demonstrate that the regulatory T cells elicited by immunizing with GAD65(524--543) are unique and distinct from those that arise from spontaneous endogenous priming, and that T cells to this limited region of GAD65 may be either regulatory or pathogenic.
authors.affiliation: Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121, USA.
authors.forename: A
authors.initials: A
authors.lastname: Quinn
authors.forename: B
authors.initials: B
authors.lastname: McInerney
authors.forename: E P
authors.initials: EP
authors.lastname: Reich
authors.forename: O
authors.initials: O
authors.lastname: Kim
authors.forename: K P
authors.initials: KP
authors.lastname: Jensen
authors.forename: E E
authors.initials: EE
authors.lastname: Sercarz
mesh_terms: D019264:Adoptive Transfer; D020816:Amino Acid Motifs / Q000235:genetics / Q000276:immunology; D000595:Amino Acid Sequence; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D002460:Cell Line; D002999:Clone Cells; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000517:prevention & control; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D019674:Genes, T-Cell Receptor beta; D005968:Glutamate Decarboxylase / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D006825:Hybridomas; D007279:Injections, Subcutaneous; D007527:Isoenzymes / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics*; D014407:Tumor Cells, Cultured
chemical_list: D018984:Epitopes, T-Lymphocyte; D007527:Isoenzymes; D010446:Peptide Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2