T-CELL TOLERANCE TOWARD A TRANSGENIC BETA-CELL ANTIGEN AND TRANSCRIPTION OF ENDOGENOUS PANCREATIC GENES IN THYMUS

Transgenic mice expressing T antigen (Tag) in pancreatic beta cells es tablish systemic tolerance toward this self-protein. The self-toleranc e in two families of rat insulin promoter (RIP)-Tag mice, expressing d ifferent levels of Tag protein, has been characterized. These mice hav e impaired antibody responses to Tag, show diminished Tag-specific T-c ell proliferation, and evidence an inability to generate Tag-specific cytotoxic T cells. The existence of systemic tolerance toward a beta-c ell-specific protein motivated examination of transgene expression in the thymus. Indeed, low levels of Tag mRNA were detected intrathymical ly. Remarkably, this expression is a valid property of the insulin gen e regulatory region, since insulin RNA was also expressed In the thymu s of nontransgenic mice. RNA for other pancreatic genes was also detec ted in the thymus, thus raising the possibility that many tissue-speci fic genes could be expressed intrathymically during immunological deve lopment and induction of self-tolerance. These results raise important questions for future research into the role of the thymus in toleranc e induction toward so-called tissue-specific antigens.