title: Lack of the phosphatase PTPN22 increases adhesion of murine regulatory T cells to improve their immunosuppressive function.
abstract: The cytoplasmic phosphatase PTPN22 (protein tyrosine phosphatase nonreceptor type 22) plays a key role in regulating lymphocyte homeostasis, which ensures that the total number of lymphocytes in the periphery remains relatively constant. Mutations in PTPN22 confer an increased risk of developing autoimmune diseases; however, the precise function of PTPN22 and how mutations contribute to autoimmunity remain controversial. Loss-of-function mutations in PTPN22 are associated with increased numbers of effector T cells and autoreactive B cells in humans and mice; however, the complete absence of PTPN22 in mice does not result in spontaneous autoimmunity. We found that PTPN22 was a key regulator of regulatory T cell (T(reg)) function that fine-tuned the signaling of the T cell receptor and integrins. PTPN22(-/-) T(regs) were more effective at immunosuppression than were wild-type T(regs), and they suppressed the activity of PTPN22(-/-) effector T cells, preventing autoimmunity. Compared to wild-type T(regs), PTPN22(-/-) T(regs) produced increased amounts of the immunosuppressive cytokine interleukin-10 and had enhanced adhesive properties mediated by the integrin lymphocyte function-associated antigen-1, processes that are critical for T(reg) function. This previously undiscovered role of PTPN22 in regulating integrin signaling and T(reg) function suggests that PTPN22 may be a useful therapeutic target for manipulating T(reg) function in human disease.
authors.affiliation: Institute for Immunology and Infection Research, The University of Edinburgh, West Mains Road, Edinburgh EH9 3JT, UK.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Brownlie
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Miosge
authors.forename: Demetrios
authors.initials: D
authors.lastname: Vassilakos
authors.forename: Lena M
authors.initials: LM
authors.lastname: Svensson
authors.forename: Andrew
authors.initials: A
authors.lastname: Cope
authors.forename: Rose
authors.initials: R
authors.lastname: Zamoyska
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000628:therapy; D002448:Cell Adhesion / Q000235:genetics / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D016023:Integrins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000201:enzymology / Q000276:immunology*
chemical_list: C556062:IL10 protein, mouse; D016023:Integrins; D016753:Interleukin-10; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; C516766:Ptpn22 protein, mouse