P. Hoglund et al., Initiation of autoimmune diabetes by developmentally regulated presentation of islet cell antigens in the pancreatic lymph nodes, J EXP MED, 189(2), 1999, pp. 331-339
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.