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Minimal Impact of a De Novo–Expressed ß-Cell Autoantigen on Spontaneous Diabetes Development in NOD Mice

¹ Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, California
² Barbara Davis Center for Childhood Diabetes, University of Colorado at Denver and Health Sciences Center, Aurora, Colorado
³ Pharmacology Research, Novo Nordisk A/S, Måløv, Denmark
⁴ Department of Immunology, The Scripps Research Institute, La Jolla, California
⁵ Klinik der Johann Wolfgang Goethe Universität, Frankfurt, Germany

Address correspondence and reprint requests to Marianne M. Martinic or Matthias G. von Herrath, Immune Regulation Lab DI-3, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037. E-mail: marmar{at}liai.org or matthias{at}liai.org

Abbreviations: CTL, cytotoxic T-lymphocyte; CNS, central nervous system; EAE, experimental autoimmune encephalomyelitis; ELISA, enzyme-linked immunosorbent assay; GAD, glutamic acid decarboxylase; HBS, hepatitis B virus polyadenylation signal; IFN-, -interferon; IGRP, islet-specific glucose-6-phosphatase catalytic subunit-related protein; IL, interleukin; LCMV, lymphocytic choriomeningitis virus; MHC, major histocompatibility complex; PBS-T, 0.05% Tween 20 in PBS; PDLN, pancreatic draining lymph node; pfu, plaque forming unit; RIP, rat insulin promoter

During an autoimmune process, the autoaggressive response spreads from the initiating autoantigen to other antigens expressed in the target organ. Based on evidence from experimental models for multiple sclerosis, such "antigenic spreading" can play an important role in the exacerbation of clinical disease. We evaluated whether pathogenesis of spontaneous diabetes in NOD mice could be accelerated in a similar way when a novel autoantigen was expressed in pancreatic ß-cells. Unexpectedly, we found that the expression of the lymphocytic choriomeningitis virus nucleoprotein only led to marginal enhancement of diabetes, although such NOD-nucleoprotein mice were not tolerant to nucleoprotein. Although the frequency of nucleoprotein-specific CD8 T-cells in the pancreatic draining lymph node was comparable with the frequency of islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)-specific T-cells, more IGRP-specific CD8 T-cells were found both systemically and in the islets where there was a fourfold increase. Interestingly, and in contrast to nucleoprotein-specific CD8 T-cells, IGRP-specific T-cells showed increased CXCR3 expression. Thus, autoreactivity toward de novo–expressed ß-cell autoantigens will not accelerate autoimmunity unless large numbers of antigen-experienced autoreactive T-cells expressing the appropriate chemokine receptors are present.

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