Prdm1 Regulates Thymic Epithelial Function To Prevent Autoimmunity

J Immunol. 2017 Aug 15;199(4):1250-1260. doi: 10.4049/jimmunol.1600941. Epub 2017 Jul 12.

Abstract

Autoimmunity is largely prevented by medullary thymic epithelial cells (TECs) through their expression and presentation of tissue-specific Ags to developing thymocytes, resulting in deletion of self-reactive T cells and supporting regulatory T cell development. The transcription factor Prdm1 has been implicated in autoimmune diseases in humans through genome-wide association studies and in mice using cell type-specific deletion of Prdm1 in T and dendritic cells. In this article, we demonstrate that Prdm1 functions in TECs to prevent autoimmunity in mice. Prdm1 is expressed by a subset of mouse TECs, and conditional deletion of Prdm1 in either Keratin 14- or Foxn1-expressing cells in mice resulted in multisymptom autoimmune pathology. Notably, the development of Foxp3+ regulatory T cells occurs normally in the absence of Blimp1. Importantly, nude mice developed anti-nuclear Abs when transplanted with Prdm1 null TECs, but not wild-type TECs, indicating that Prdm1 functions in TECs to regulate autoantibody production. We show that Prdm1 acts independently of Aire, a crucial transcription factor implicated in medullary TEC function. Collectively, our data highlight a previously unrecognized role for Prdm1 in regulating thymic epithelial function.

MeSH terms

  • Animals
  • Antibodies, Antinuclear / biosynthesis
  • Antibodies, Antinuclear / immunology
  • Autoantibodies / biosynthesis
  • Autoantibodies / immunology
  • Autoimmunity*
  • Epithelial Cells / immunology
  • Epithelial Cells / metabolism
  • Epithelial Cells / physiology
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Regulation
  • Keratin-14 / genetics
  • Keratin-14 / metabolism
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Nude
  • Positive Regulatory Domain I-Binding Factor 1
  • T-Lymphocytes / immunology*
  • T-Lymphocytes, Regulatory / immunology
  • Thymus Gland / cytology
  • Thymus Gland / immunology*
  • Transcription Factors / deficiency
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism*

Substances

  • APECED protein
  • Antibodies, Antinuclear
  • Autoantibodies
  • Forkhead Transcription Factors
  • Keratin-14
  • Krt14 protein, mouse
  • Prdm1 protein, mouse
  • Transcription Factors
  • Whn protein
  • Positive Regulatory Domain I-Binding Factor 1