J. Exp. Med., Volume 189, Number 2, January 18, 1999 331-339

Initiation of Autoimmune Diabetes by Developmentally Regulated Presentation of Islet Cell Antigens in the Pancreatic Lymph Nodes

By Petter Höglund,^* Justine Mintern, Caroline Waltzinger,^* William Heath, Christophe Benoist,^* and Diane Mathis^*

From the ^* Institut de Génétique et de Biologie Moléculaire et Cellulaire (CNRS/INSERM/ULP), Strasbourg, 67404 Illkirch Cedex, France; and the  Walter and Eliza Hall Institute for Medical Research, Melbourne, Victoria 3050, Australia

Little is known about the events triggering lymphocyte invasion of the pancreatic islets in prelude to autoimmune diabetes. For example, where islet-reactive T cells first encounter antigen has not been identified. We addressed this issue using BDC2.5 T cell receptor transgenic mice, which express a receptor recognizing a natural islet beta cell antigen. In BDC2.5 animals, activated T cells were found only in the islets and the lymph nodes draining them, and there was a close temporal correlation between lymph node T cell activation and islet infiltration. When naive BDC2.5 T cells were transferred into nontransgenic recipients, proliferating cells were observed only in pancreatic lymph nodes, and this occurred significantly before insulitis was detectable. Surprisingly, proliferation was not seen in 10-day-old recipients. This age-dependent dichotomy was reproduced in a second transfer system based on an unrelated antigen artificially expressed on beta cells. We conclude that beta cell antigens are transported specifically to pancreatic lymph nodes, where they trigger reactive T cells to invade the islets. Systemic or extrapancreatic T cell priming, indicative of activation via molecular mimicry or superantigens, was not seen. Compromised presentation of beta cell antigens in the pancreatic lymph nodes of juvenile animals may be the root of a first "checkpoint" in diabetes progression.

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• Greeley, S. A. W., Moore, D. J., Noorchashm, H., Noto, L. E., Rostami, S. Y., Schlachterman, A., Song, H. K., Koeberlein, B., Barker, C. F., Naji, A. (2001). Impaired Activation of Islet-Reactive CD4 T Cells in Pancreatic Lymph Nodes of B Cell-Deficient Nonobese Diabetic Mice. J. Immunol. 167: 4351-4357 [Abstract] [Full Text]  
• Kelemen, K., Wegmann, D. R., Hutton, J. C. (2001). T-Cell Epitope Analysis on the Autoantigen Phogrin (IA-2{beta}) in the Nonobese Diabetic Mouse. Diabetes 50: 1729-1734 [Abstract] [Full Text]  
• Mikulowska-Mennis, A., Xu, B., Berberian, J. M., Michie, S. A. (2001). Lymphocyte Migration to Inflamed Lacrimal Glands Is Mediated by Vascular Cell Adhesion Molecule-1/{alpha}4{beta}1 Integrin, Peripheral Node Addressin/L-Selectin, and Lymphocyte Function-Associated Antigen-1 Adhesion Pathways. Am. J. Pathol. 159: 671-681 [Abstract] [Full Text]  
• Weaver, D. J. Jr., Liu, B., Tisch, R. (2001). Plasmid DNAs Encoding Insulin and Glutamic Acid Decarboxylase 65 Have Distinct Effects on the Progression of Autoimmune Diabetes in Nonobese Diabetic Mice. J. Immunol. 167: 586-592 [Abstract] [Full Text]  
• Ettinger, R., Munson, S. H., Chao, C.-C., Vadeboncoeur, M., Toma, J., McDevitt, H. O. (2001). A Critical Role for Lymphotoxin-{beta} Receptor in the Development of Diabetes in Nonobese Diabetic Mice. J. Exp. Med. 193: 1333-1340 [Abstract] [Full Text]  
• Tisch, R., Wang, B., Atkinson, M. A., Serreze, D. V., Friedline, R. (2001). A Glutamic Acid Decarboxylase 65-Specific Th2 Cell Clone Immunoregulates Autoimmune Diabetes in Nonobese Diabetic Mice. J. Immunol. 166: 6925-6936 [Abstract] [Full Text]  
• Rennert, P. D., Hochman, P. S., Flavell, R. A., Chaplin, D. D., Jayaraman, S., Browning, J. L., Fu, Y.-X. (2001). Essential Role of Lymph Nodes in Contact Hypersensitivity Revealed in Lymphotoxin-{alpha}-deficient Mice. J. Exp. Med. 193: 1227-1238 [Abstract] [Full Text]  
• Alard, P., Thompson, C., Agersborg, S. S., Thatte, J., Setiady, Y., Samy, E., Tung, K. S. K. (2001). Endogenous Oocyte Antigens Are Required for Rapid Induction and Progression of Autoimmune Ovarian Disease Following Day-3 Thymectomy. J. Immunol. 166: 4363-4369 [Abstract] [Full Text]  
• Laloux, V., Beaudoin, L., Jeske, D., Carnaud, C., Lehuen, A. (2001). NK T Cell-Induced Protection Against Diabetes in V{{alpha}}14-J{{alpha}}281 Transgenic Nonobese Diabetic Mice Is Associated with a Th2 Shift Circumscribed Regionally to the Islets and Functionally to Islet Autoantigen. J. Immunol. 166: 3749-3756 [Abstract] [Full Text]  

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