The autoimmunity-associated gene PTPN22 potentiates toll-like receptor-driven, type 1 interferon-dependent immunity

Immunity. 2013 Jul 25;39(1):111-22. doi: 10.1016/j.immuni.2013.06.013. Epub 2013 Jul 18.

Abstract

Immune cells sense microbial products through Toll-like receptors (TLR), which trigger host defense responses including type 1 interferons (IFNs) secretion. A coding polymorphism in the protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene is a susceptibility allele for human autoimmune and infectious disease. We report that Ptpn22 selectively regulated type 1 IFN production after TLR engagement in myeloid cells. Ptpn22 promoted host antiviral responses and was critical for TLR agonist-induced, type 1 IFN-dependent suppression of inflammation in colitis and arthritis. PTPN22 directly associated with TNF receptor-associated factor 3 (TRAF3) and promotes TRAF3 lysine 63-linked ubiquitination. The disease-associated PTPN22W variant failed to promote TRAF3 ubiquitination, type 1 IFN upregulation, and type 1 IFN-dependent suppression of arthritis. The findings establish a candidate innate immune mechanism of action for a human autoimmunity "risk" gene in the regulation of host defense and inflammation.

Publication types

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

MeSH terms

  • Animals
  • Arthritis / genetics
  • Arthritis / immunology
  • Autoimmunity / genetics
  • Autoimmunity / immunology*
  • Cell Line
  • Cells, Cultured
  • Colitis / chemically induced
  • Colitis / genetics
  • Colitis / immunology
  • Dextran Sulfate / immunology
  • HEK293 Cells
  • Host-Pathogen Interactions / immunology
  • Humans
  • Immunity / genetics
  • Immunity / immunology*
  • Immunoblotting
  • Interferon Type I / genetics
  • Interferon Type I / immunology*
  • Interferon Type I / metabolism
  • Lymphocytic Choriomeningitis / genetics
  • Lymphocytic Choriomeningitis / immunology
  • Lymphocytic Choriomeningitis / virology
  • Lymphocytic choriomeningitis virus / immunology
  • Lymphocytic choriomeningitis virus / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Myeloid Cells / immunology
  • Myeloid Cells / metabolism
  • Protein Tyrosine Phosphatase, Non-Receptor Type 22 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 22 / immunology*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 22 / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • TNF Receptor-Associated Factor 3 / genetics
  • TNF Receptor-Associated Factor 3 / immunology
  • TNF Receptor-Associated Factor 3 / metabolism
  • Toll-Like Receptors / genetics
  • Toll-Like Receptors / immunology*
  • Toll-Like Receptors / metabolism
  • Ubiquitination / immunology

Substances

  • Interferon Type I
  • TNF Receptor-Associated Factor 3
  • Toll-Like Receptors
  • Dextran Sulfate
  • Protein Tyrosine Phosphatase, Non-Receptor Type 22
  • Ptpn22 protein, mouse