Regulation of medullary thymic epithelial cell differentiation and function by the signaling protein Sin.
Medullary thymic epithelial cells (mTECs) play an important role in T cell tolerance and prevention of autoimmunity. Mice deficient in expression of the signaling protein Sin exhibit exaggerated immune responses and multitissue inflammation. Here, we show that Sin is expressed in the thymic stroma, specifically in mTECs. Sin deficiency led to thymic stroma-dependent autoimmune manifestations shown by radiation chimeras and thymic transplants in nude mice, and associated with defective mTEC-mediated elimination of thymocytes in a T cell receptor transgenic model of negative selection. Lack of Sin expression correlated with a disorganized medullary architecture and fewer functionally mature mTECs under steady-state conditions. Additionally, Sin deficiency inhibited the expansion of mTECs in response to in vivo administration of keratinocyte growth factor (KGF). These results identify Sin as a novel regulator of mTEC development and T cell tolerance, and suggest that Sin is important for homeostatic maintenance of the medullary epithelium in the adult thymus.
Danzl
Nichole M
NM
Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Donlin
Laura T
LT
Alexandropoulos
Konstantina
K
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015551:Autoimmunity / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology / Q000502:physiology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D051523:Fibroblast Growth Factor 7 / Q000494:pharmacology; D006706:Homeostasis; D007108:Immune Tolerance; D007156:Immunologic Memory; D007165:Immunosuppression Therapy; D007249:Inflammation / Q000209:etiology; D008285:Major Histocompatibility Complex; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*
D048868:Adaptor Proteins, Signal Transducing; C097281:Efs protein, mouse; D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell; D051523:Fibroblast Growth Factor 7
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