Initiation of autoimmune diabetes by developmentally regulated presentation of islet cell antigens in the pancreatic lymph nodes

Little is known about the events triggering lymphocyte invasion of the panc reatic islets in prelude to autoimmune diabetes. For example, where islet-r eactive T cells first encounter antigen has not been identified. We address ed 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 draini ng them, and there was a close temporal correlation between lymph node T ce ll activation and islet infiltration. When naive BDC2.5 T cells were transf erred into nontransgenic recipients, proliferating cells were observed only in pancreatic lymph nodes, and this occurred significantly before insuliti s was detectable. Surprisingly, proliferation was not seen in 10-day-old re cipients. 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 pancrea tic lymph nodes, where they trigger reactive T cells to invade the islets. Systemic or extrapancreatic T cell priming, indicative of activation via mo lecular mimicry or superantigens, was not seen. Compromised presentation of beta cell antigens in the pancreatic lymph nodes of juvenile animals may b e the root of a first "checkpoint" in diabetes progression.