T-Cell Tolerance Toward a Transgenic β-Cell Antigen and Transcription of Endogenous Pancreatic Genes in Thymus

• Published in: Proceedings of the National Academy of Sciences - PNAS 1994-07, Vol.91 (14), p.6707-6711
• Main Authors: Jolicoeur, Christine, Hanahan, Douglas, Smith, Kathleen M.
• Format: Article
• Language: English
• Subjects: Animals; Antigens; Antigens, Viral, Tumor - biosynthesis; B lymphocytes; Base Sequence; Brain - metabolism; Complementary DNA; Crosses, Genetic; Cytotoxicity, Immunologic; DNA Primers; Female; Gene Expression; Genes; Immune tolerance; Immune Tolerance - genetics; Insulin; Islets of Langerhans - immunology; Islets of Langerhans - metabolism; Liver - metabolism; Lymphocyte Activation; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Transgenic; Molecular Sequence Data; Organ Specificity; Pancreas; Pancreas - metabolism; RNA; T lymphocytes; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; T-Lymphocytes, Cytotoxic - immunology; Thymus Gland - immunology; Thymus Gland - metabolism; Transgenic animals
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.91.14.6707

Transgenic mice expressing T antigen (Tag) in pancreatic β 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 β-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.