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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.

Key Words: autoimmunity • antigen presentation • T lymphocytes • transgenic mice • nonobese diabetic

Abbreviations used: CFSE, 5,6-carboxyfluorescein diacetate succinimidyl ester; DC, dendritic cell; IDDM, insulin-dependent diabetes mellitus; IIL, intraislet lymphocyte; ILN, inguinal lymph node; MLN, mesenteric lymph node; NOD, nonobese diabetic; OT-I, OVA-specific CD8⁺ T cells; PLN, pancreatic lymph node; RAG, recombination activating gene; RIP, rat insulin promoter; RLN, renal lymph node; tg, transgenic.

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