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      Isolation and characterization of proinsulin-producing medullary thymic epithelial cell clones.


      Animals, Antibodies, immunology, Cell Separation, Cells, Cultured, Clone Cells, Epithelial Cells, cytology, metabolism, Flow Cytometry, methods, Glucokinase, biosynthesis, Glucose Transporter Type 2, Homeodomain Proteins, Insulin, Lymphotoxin-alpha, Lymphotoxin-beta, Membrane Proteins, Mice, Proinsulin, Reverse Transcriptase Polymerase Chain Reaction, Thymus Gland, Trans-Activators, Transcription Factors

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          Proinsulin, like many tissue-specific antigens, is expressed by rare (1-3%) cells of the thymus medullary stroma, presumably for the purpose of self-tolerance. Levels of this expression are associated with type 1 diabetes susceptibility in humans and in the NOD mouse. To further understand the mechanism of central tolerance induction by these rare cells, we have isolated and cultured two proinsulin-producing epithelial cell clones from murine thymus. These cells have a typical epithelial morphology and, by flow cytometry, a surface phenotype representative of mature thymic medullary epithelial cells (G8.8(+)/UEA-1(+)/DEC205(-)/CD45(-)/MHC II(+)). By RT-PCR, they express predominantly Ins2 as opposed to Ins1, as does whole thymus. Expression of the transcription factor Aire, implicated in enhancing promiscuous thymic expression of tissue-specific antigens, fell to very low levels after a few passages but increased 20-fold upon exposure to an agonistic anti-lymphotoxin B antibody, concurrent with 2.5-fold enhanced insulin expression. RNA of Pdx-1, Glut-2, and Gck was detectable by RT-PCR in whole thymus but not in the clones, suggesting thymic proinsulin expression is Pdx-1 independent and that Pdx-1, Glut-2, and Gck are likely expressed in the thymus as antigens, not as regulatory molecules.

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