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The Journal of Immunology, 2001, 166: 2982-2991.
Copyright © 2001 by The American Association of Immunologists

Regulatory and Effector CD4 T Cells in Nonobese Diabetic Mice Recognize Overlapping Determinants on Glutamic Acid Decarboxylase and Use Distinct V{beta} Genes1

Anthony Quinn*, Brigid McInerney*, Eva P. Reich{dagger}, Olivia Kim{ddagger}, Kent P. Jensen*,{ddagger} and Eli E. Sercarz2,*

* Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121, {dagger} Anergen, Redwood City, CA 94063; and {ddagger} Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095

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-Ag7-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.




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