Expression of A20 by dendritic cells preserves immune homeostasis and prevents colitis and spondyloarthritis

Nat Immunol. 2011 Oct 23;12(12):1184-93. doi: 10.1038/ni.2135.

Abstract

Dendritic cells (DCs), which are known to support immune activation during infection, may also regulate immune homeostasis in resting animals. Here we show that mice lacking the ubiquitin-editing molecule A20 specifically in DCs spontaneously showed DC activation and population expansion of activated T cells. Analysis of DC-specific epistasis in compound mice lacking both A20 and the signaling adaptor MyD88 specifically in DCs showed that A20 restricted both MyD88-independent signals, which drive activation of DCs and T cells, and MyD88-dependent signals, which drive population expansion of T cells. In addition, mice lacking A20 specifically in DCs spontaneously developed lymphocyte-dependent colitis, seronegative ankylosing arthritis and enthesitis, conditions stereotypical of human inflammatory bowel disease (IBD). Our findings indicate that DCs need A20 to preserve immune quiescence and suggest that A20-dependent DC functions may underlie IBD and IBD-associated arthritides.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Colitis / immunology*
  • Colitis / pathology
  • Colitis / prevention & control
  • Crohn Disease / genetics
  • Cysteine Endopeptidases
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism
  • Genetic Predisposition to Disease
  • Homeostasis / immunology
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Lymphatic Diseases / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Myeloid Differentiation Factor 88 / metabolism
  • Nuclear Proteins / genetics
  • Polymorphism, Single Nucleotide
  • Signal Transduction
  • Splenomegaly / genetics
  • Spondylitis, Ankylosing / immunology*
  • Spondylitis, Ankylosing / pathology
  • Spondylitis, Ankylosing / prevention & control
  • T-Lymphocytes / immunology
  • Tumor Necrosis Factor alpha-Induced Protein 3
  • Ubiquitin-Protein Ligases / genetics*
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • Myeloid Differentiation Factor 88
  • Nuclear Proteins
  • Ubiquitin-Protein Ligases
  • TNFAIP3 protein, human
  • Tumor Necrosis Factor alpha-Induced Protein 3
  • Cysteine Endopeptidases
  • Tnfaip3 protein, mouse