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.
Yaya Wang  1 ,  Iftach Shaked ,  Stephanie M Stanford ,  Wenbo Zhou ,  Julie M Curtsinger ,  Zbigniew Mikulski ,  Zachary R Shaheen ,  Genhong Cheng ,  Kristy Sawatzke ,  Amanda M Campbell ,  Jennifer L Auger ,  Hatice Bilgic ,  Fernanda M Shoyama ,  David O Schmeling ,  Henry H Balfour Jr ,  Kiminori Hasegawa ,  Andrew C Chan ,  John A Corbett ,  Bryce A Binstadt ,  Matthew F Mescher ,  Klaus Ley ,  Nunzio Bottini ,  Erik J Peterson
Affiliations
  • 1. Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA.
PMID: 23871208 DOI: 10.1016/j.immuni.2013.06.013
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.