Regulation of medullary thymic epithelial cell differentiation and function by the signaling protein Sin

J Exp Med. 2010 May 10;207(5):999-1013. doi: 10.1084/jem.20092384. Epub 2010 Apr 19.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Autoimmunity / immunology
  • Cell Differentiation / immunology
  • Cell Differentiation / physiology
  • Epithelial Cells / cytology
  • Epithelial Cells / drug effects
  • Epithelial Cells / immunology
  • Fibroblast Growth Factor 7 / pharmacology
  • Homeostasis
  • Immune Tolerance
  • Immunologic Memory
  • Immunosuppression
  • Inflammation / etiology
  • Major Histocompatibility Complex
  • Mice
  • Mice, Knockout
  • Mice, Nude
  • Phosphoproteins / genetics
  • Phosphoproteins / physiology*
  • Receptors, Antigen, T-Cell / immunology
  • Signal Transduction / drug effects
  • Signal Transduction / immunology
  • T-Lymphocytes / immunology
  • Thymus Gland / cytology*
  • Thymus Gland / drug effects
  • Thymus Gland / immunology*

Substances

  • Efs protein, mouse
  • Phosphoproteins
  • Receptors, Antigen, T-Cell
  • Fibroblast Growth Factor 7