Pancreatic gene expression in rare cells of thymic medulla: evidence for functional contribution to T cell tolerance.
We report the initial characterization of rare cells within the thymus that express 'peripheral' self-antigens and are capable of inducing partial tolerance to a model protein. Mice from two transgenic families that express SV40 T antigen (Tag) in pancreatic islet beta cells under control of a rat insulin promoter (RIP) develop T cell tolerance toward this neo-self antigen. These mice express low levels of Tag mRNA in the thymus. Transplantation of thymus from tolerant RIP-Tag mice into athymic hosts is sufficient to confer tolerance by CD4+ Th cells and elicits variable tolerance by CD8+ cytotoxic T cells. Thymic medulla is shown to contain rare cells that express the endogenous insulin and somatostatin genes, and in the transgenic animals, Tag. These cells are referred to as 'peripheral antigen-expressing' (PAE) cells. Thymic cell fractionation reveals the PAE cells expressing insulin and Tag to be present in a fraction enriched for non-lymphoid, MHC class II+ cells. Notably, absence of thymic expression of the RIP-Tag gene in another transgenic family correlates with failure to establish self-tolerance and susceptibility to autoimmunity. Thus, expression of tissue-restricted genes such as insulin in PAE cells of thymic medulla may serve to limit development of potentially autoimmune T cells.
Smith
K M
KM
Department of Biochemistry and Biophysics, University of California, San Francisco 94143-0534, USA.
Olson
D C
DC
Hirose
R
R
Hanahan
D
D
D000818:Animals; D000957:Antigens, Viral, Tumor / Q000096:biosynthesis / Q000235:genetics; D001327:Autoimmune Diseases / Q000235:genetics / Q000378:metabolism; D002469:Cell Separation; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D007108:Immune Tolerance / Q000235:genetics*; D007150:Immunohistochemistry; D007328:Insulin / Q000235:genetics; D007515:Islets of Langerhans / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000378:metabolism; D051381:Rats; D013539:Simian virus 40 / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*
D000957:Antigens, Viral, Tumor; D007328:Insulin; D012333:RNA, Messenger