The ubiquitin ligase Peli1 negatively regulates T cell activation and prevents autoimmunity

Nat Immunol. 2011 Aug 28;12(10):1002-9. doi: 10.1038/ni.2090.

Abstract

T cell activation is subject to tight regulation to avoid inappropriate responses to self antigens. Here we show that genetic deficiency in the ubiquitin ligase Peli1 caused hyperactivation of T cells and rendered T cells refractory to suppression by regulatory T cells and transforming growth factor-β (TGF-β). As a result, Peli1-deficient mice spontaneously developed autoimmunity characterized by multiorgan inflammation and autoantibody production. Peli1 deficiency resulted in the nuclear accumulation of c-Rel, a member of the NF-κB family of transcription factors with pivotal roles in T cell activation. Peli1 negatively regulated c-Rel by mediating its Lys48 (K48) ubiquitination. Our results identify Peli1 as a critical factor in the maintenance of peripheral T cell tolerance and demonstrate a previously unknown mechanism of c-Rel regulation.

Publication types

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

MeSH terms

  • Animals
  • Autoimmunity*
  • CD28 Antigens / physiology
  • Lymphocyte Activation*
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B / metabolism
  • Nuclear Proteins / physiology*
  • Proto-Oncogene Proteins c-rel / metabolism
  • Receptors, Antigen, T-Cell / physiology
  • T-Lymphocytes / immunology*
  • T-Lymphocytes, Regulatory / physiology
  • Transforming Growth Factor beta / physiology
  • Ubiquitin-Protein Ligases
  • Ubiquitination

Substances

  • CD28 Antigens
  • NF-kappa B
  • Nuclear Proteins
  • Proto-Oncogene Proteins c-rel
  • Receptors, Antigen, T-Cell
  • Transforming Growth Factor beta
  • Ubiquitin-Protein Ligases
  • Peli1 protein, mouse