title: Autoimmunity-associated protein tyrosine phosphatase PEP negatively regulates IFN-α receptor signaling.
abstract: The protein tyrosine phosphatase PTPN22(C1858T) allelic polymorphism is associated with increased susceptibility for development of systemic lupus erythematosus (SLE) and other autoimmune diseases. PTPN22 (also known as LYP) and its mouse orthologue PEP play important roles in antigen and Toll-like receptor signaling in immune cell functions. We demonstrate here that PEP also plays an important inhibitory role in interferon-α receptor (IFNAR) signaling in mice. PEP co-immunoprecipitates with components of the IFNAR signaling complex. Pep(-/-) hematopoietic progenitors demonstrate increased IFNAR signaling, increased IFN-inducible gene expression, and enhanced proliferation and activation compared to Pep(+/+) progenitors in response to IFN-α. In addition, Pep(-/-) mice treated with IFN-α display a profound defect in hematopoiesis, resulting in anemia, thrombocytopenia, and neutropenia when compared to IFN-α-treated Pep(+/+) mice. As SLE patients carrying the PTPN22(C1858T) risk variant have higher serum IFN-α activity, these data provide a molecular basis for how type I IFNs and PTPN22 may cooperate to contribute to lupus-associated cytopenias.
authors.affiliation: Department of Immunology, Department of Translational Immunology, and Department of Pathology, Genentech, Inc., South San Francisco, CA 94080.
authors.forename: Derek A
authors.initials: DA
authors.lastname: Holmes
authors.affiliation: Department of Immunology, Department of Translational Immunology, and Department of Pathology, Genentech, Inc., South San Francisco, CA 94080.
authors.forename: Eric
authors.initials: E
authors.lastname: Suto
authors.affiliation: Department of Immunology, Department of Translational Immunology, and Department of Pathology, Genentech, Inc., South San Francisco, CA 94080.
authors.forename: Wyne P
authors.initials: WP
authors.lastname: Lee
authors.affiliation: Department of Immunology, Department of Translational Immunology, and Department of Pathology, Genentech, Inc., South San Francisco, CA 94080.
authors.forename: Qinglin
authors.initials: Q
authors.lastname: Ou
authors.affiliation: Department of Immunology, Department of Translational Immunology, and Department of Pathology, Genentech, Inc., South San Francisco, CA 94080.
authors.forename: Qian
authors.initials: Q
authors.lastname: Gong
authors.affiliation: Department of Immunology, Department of Translational Immunology, and Department of Pathology, Genentech, Inc., South San Francisco, CA 94080.
authors.forename: Hamish R C
authors.initials: HR
authors.lastname: Smith
authors.affiliation: Department of Immunology, Department of Translational Immunology, and Department of Pathology, Genentech, Inc., South San Francisco, CA 94080.
authors.forename: Patrick
authors.initials: P
authors.lastname: Caplazi
authors.affiliation: Department of Immunology, Department of Translational Immunology, and Department of Pathology, Genentech, Inc., South San Francisco, CA 94080 acc@gene.com.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Chan
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D047468:Immunoprecipitation; D016898:Interferon-alpha / Q000097:blood; D008180:Lupus Erythematosus, Systemic / Q000201:enzymology*; D051379:Mice; D018345:Mice, Knockout; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics / Q000378:metabolism*; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D016898:Interferon-alpha; D053633:Receptor, Interferon alpha-beta; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; C516766:Ptpn22 protein, mouse