The Autoimmunity-associated Gene PTPN22 Potentiates Toll-like Receptor-driven, Type 1 Interferon-dependent Immunity

Overview

Journal Immunity

Publisher Cell Press

Specialty Allergy & Immunology

Date 2013 Jul 23

PMID 23871208

Citations 126

Authors

Yaya Wang

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

Soon will be listed here.

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.

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References

Zarnegar B, Wang Y, Mahoney D, Dempsey P, Cheung H, He J . Noncanonical NF-kappaB activation requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2 and TRAF3 and the kinase NIK. Nat Immunol. 2008; 9(12):1371-8. PMC: 2676931. DOI: 10.1038/ni.1676. View

Ji H, Pettit A, Ohmura K, Ortiz-Lopez A, Duchatelle V, Degott C . Critical roles for interleukin 1 and tumor necrosis factor alpha in antibody-induced arthritis. J Exp Med. 2002; 196(1):77-85. PMC: 2194010. DOI: 10.1084/jem.20020439. View

Gitlin L, Barchet W, Gilfillan S, Cella M, Beutler B, Flavell R . Essential role of mda-5 in type I IFN responses to polyriboinosinic:polyribocytidylic acid and encephalomyocarditis picornavirus. Proc Natl Acad Sci U S A. 2006; 103(22):8459-64. PMC: 1464000. DOI: 10.1073/pnas.0603082103. View

Zhou S, Cerny A, Zacharia A, Fitzgerald K, Kurt-Jones E, Finberg R . Induction and inhibition of type I interferon responses by distinct components of lymphocytic choriomeningitis virus. J Virol. 2010; 84(18):9452-62. PMC: 2937596. DOI: 10.1128/JVI.00155-10. View

He J, Zarnegar B, Oganesyan G, Saha S, Yamazaki S, Doyle S . Rescue of TRAF3-null mice by p100 NF-kappa B deficiency. J Exp Med. 2006; 203(11):2413-8. PMC: 2118128. DOI: 10.1084/jem.20061166. View

Arimura Y, Yagi J . Comprehensive expression profiles of genes for protein tyrosine phosphatases in immune cells. Sci Signal. 2010; 3(137):rs1. DOI: 10.1126/scisignal.2000966. View

Boettler T, von Herrath M . Protection against or triggering of Type 1 diabetes? Different roles for viral infections. Expert Rev Clin Immunol. 2010; 7(1):45-53. PMC: 3077770. DOI: 10.1586/eci.10.91. View

Sobel D, Ahvazi B . Alpha-interferon inhibits the development of diabetes in NOD mice. Diabetes. 1998; 47(12):1867-72. DOI: 10.2337/diabetes.47.12.1867. View

Rhee I, Veillette A . Protein tyrosine phosphatases in lymphocyte activation and autoimmunity. Nat Immunol. 2012; 13(5):439-47. DOI: 10.1038/ni.2246. View

10.

Tseng P, Matsuzawa A, Zhang W, Mino T, Vignali D, Karin M . Different modes of ubiquitination of the adaptor TRAF3 selectively activate the expression of type I interferons and proinflammatory cytokines. Nat Immunol. 2009; 11(1):70-5. PMC: 2872790. DOI: 10.1038/ni.1819. View

11.

Cloutier J, Veillette A . Cooperative inhibition of T-cell antigen receptor signaling by a complex between a kinase and a phosphatase. J Exp Med. 1999; 189(1):111-21. PMC: 1887684. DOI: 10.1084/jem.189.1.111. View

12.

Yu X, Sun J, He Y, Guo X, Liu S, Zhou B . Structure, inhibitor, and regulatory mechanism of Lyp, a lymphoid-specific tyrosine phosphatase implicated in autoimmune diseases. Proc Natl Acad Sci U S A. 2007; 104(50):19767-72. PMC: 2148373. DOI: 10.1073/pnas.0706233104. View

13.

Takeuchi O, Akira S . Pattern recognition receptors and inflammation. Cell. 2010; 140(6):805-20. DOI: 10.1016/j.cell.2010.01.022. View

14.

Gregersen P, Lee H, Batliwalla F, Begovich A . PTPN22: setting thresholds for autoimmunity. Semin Immunol. 2006; 18(4):214-23. DOI: 10.1016/j.smim.2006.03.009. View

15.

Korganow A, Ji H, Mangialaio S, Duchatelle V, Pelanda R, Martin T . From systemic T cell self-reactivity to organ-specific autoimmune disease via immunoglobulins. Immunity. 1999; 10(4):451-61. DOI: 10.1016/s1074-7613(00)80045-x. View

16.

Hacker H, Tseng P, Karin M . Expanding TRAF function: TRAF3 as a tri-faced immune regulator. Nat Rev Immunol. 2011; 11(7):457-68. DOI: 10.1038/nri2998. View

17.

Chen Z . Ubiquitination in signaling to and activation of IKK. Immunol Rev. 2012; 246(1):95-106. PMC: 3549672. DOI: 10.1111/j.1600-065X.2012.01108.x. View

18.

Curtsinger J, Valenzuela J, Agarwal P, Lins D, Mescher M . Type I IFNs provide a third signal to CD8 T cells to stimulate clonal expansion and differentiation. J Immunol. 2005; 174(8):4465-9. DOI: 10.4049/jimmunol.174.8.4465. View

19.

Gonzalez-Navajas J, Lee J, David M, Raz E . Immunomodulatory functions of type I interferons. Nat Rev Immunol. 2012; 12(2):125-35. PMC: 3727154. DOI: 10.1038/nri3133. View

20.

Cloutier J, Veillette A . Association of inhibitory tyrosine protein kinase p50csk with protein tyrosine phosphatase PEP in T cells and other hemopoietic cells. EMBO J. 1996; 15(18):4909-18. PMC: 452228. View