Ectopic expression and presentation of diabetogenic antigens in the lymph nodes of NOD mice. (171.10)

Abstract

Abstract Ectopic expression and presentation of peripheral tissue antigens (PTAs) in lymph node stromal cells has been shown to contribute to the maintenance of peripheral tolerance. During disease progression in non-obese diabetic (NOD) mice, at 12 weeks of age (the onset of destructive insulitis), expression of genes encoding many PTAs (including insulin and chromogranin A) as well as the function of the transcription regulator Deaf1, are diminished in the pancreatic lymph nodes (PLNs). We observed a defect in insulin presentation in NOD mice both in vivo (in adoptive transfer experiments) and in vitro (using purified stromal cells) compared to 12-wk old diabetes-resistant (NOD x NOD.B10) F1 mice. We identified two stromal cell subsets within the gp38+ CD31- fibroblastic reticular cells and the gp38- CD31- double negative (DN) population that can express and present insulin to CD4 T cells. Data generated to date suggest that Deaf1 controls the expression of insulin at least in DN cells. Inflammation can induce the splicing of Deaf1 mRNA into a dominant negative isoform in the PLNs. Preliminary data suggest that a substantial proportion of T cells stimulated in vivo or by stromal cells ex vivo induce Foxp3 expression. Thus, diminished PTA expression and presentation in 12-wk old NOD mice may impair the maintenance of peripheral tolerance and may explain the subsequent progression from peri-insulitis to destructive insulitis and hyperglycemia.