The Autoimmunity-Associated Gene PTPN22 Potentiates Toll-like Receptor-Driven, Type 1 Interferon-Dependent Immunity

Yaya Wang, Iftach Shaked, StephanieM Stanford, Wenbo Zhou, JulieM Curtsinger, Zbigniew Mikulski, ZacharyR Shaheen, Genhong Cheng, Kristy Sawatzke, AmandaM Campbell, JenniferL Auger, Hatice Bilgic, FernandaM Shoyama, DavidO Schmeling, HenryH Balfour, Kiminori Hasegawa, AndrewC Chan, JohnA Corbett, BryceA Binstadt, MatthewF MescherKlaus Ley, Nunzio Bottini, ErikJ Peterson

Research output: Contribution to journalArticlepeer-review

122 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)111-122
Number of pages12
JournalImmunity
Volume39
Issue number1
DOIs
StatePublished - Jul 25 2013

Bibliographical note

Funding Information:
We thank G. Koretzky (University of Pennsylvania) for critical reading of the manuscript, the S. Fahrenkrug laboratory and Mouse Genetics Laboratory (University of Minnesota, UMN) for assistance with generation of transgenic mice, and Z. Zhang (Indiana University) for providing PTPN22 inhibitors. The D. Masopust (UMN) and M. von Herrath (LIAI) laboratories assisted with viral infection protocols. M. Jenkins (UMN) provided reagents. J. Gonzalez-Navajas (LIAI) provided technical assistance with ubiquitination assays. S. DuCloux-Potter provided secretarial assistance. This work was supported by grants from the National Institutes of Health (NIH) R01AR057781, the American College of Rheumatology Within Our Reach Campaign, the American Diabetes Association, the Alliance for Lupus Research, and Lupus Foundation of Minnesota (to E.J.P.), the International Center for Antiviral Research and Epidemiology, UMN (to H.H.B.), and NIH R01AI070544 (to N.B.). S.M.S was supported by a postdoctoral fellowship from the Juvenile Diabetes Research Foundation. A.C.C. is an employee of Genentech. This is the publication #1622 from the La Jolla Institute for Allergy and Immunology.

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