T-cell tolerance toward a transgenic beta-cell antigen and transcription of endogenous pancreatic genes in thymus.

TLDR

Transgenic mice expressing the T antigen (Tag) in pancreatic β‑cells develop systemic tolerance to this self‑protein. The study aimed to investigate whether Tag expression occurs in the thymus to explain this systemic tolerance. Self‑tolerance was characterized in two RIP‑Tag mouse families expressing different Tag levels. The RIP‑Tag mice showed impaired antibody responses, reduced Tag‑specific T‑cell proliferation, and failed to generate Tag‑specific cytotoxic T cells, while low intrathymic Tag mRNA and insulin RNA were detected, and additional pancreatic genes were expressed in the thymus, suggesting that many tissue‑specific genes may be expressed intrathymically to promote tolerance and raising questions about thymic roles in tolerance induction.

Abstract

Transgenic mice expressing T antigen (Tag) in pancreatic beta cells establish systemic tolerance toward this self-protein. The self-tolerance in two families of rat insulin promoter (RIP)-Tag mice, expressing different levels of Tag protein, has been characterized. These mice have impaired antibody responses to Tag, show diminished Tag-specific T-cell proliferation, and evidence an inability to generate Tag-specific cytotoxic T cells. The existence of systemic tolerance toward a beta-cell-specific protein motivated examination of transgene expression in the thymus. Indeed, low levels of Tag mRNA were detected intrathymically. Remarkably, this expression is a valid property of the insulin gene regulatory region, since insulin RNA was also expressed in the thymus of nontransgenic mice. RNA for other pancreatic genes was also detected in the thymus, thus raising the possibility that many tissue-specific genes could be expressed intrathymically during immunological development and induction of self-tolerance. These results raise important questions for future research into the role of the thymus in tolerance induction toward so-called tissue-specific antigens.