title: Superresolution imaging of the cytoplasmic phosphatase PTPN22 links integrin-mediated T cell adhesion with autoimmunity.
abstract: Integrins are heterodimeric transmembrane proteins that play a fundamental role in the migration of leukocytes to sites of infection or injury. We found that protein tyrosine phosphatase nonreceptor type 22 (PTPN22) inhibits signaling by the integrin lymphocyte function-associated antigen-1 (LFA-1) in effector T cells. PTPN22 colocalized with its substrates at the leading edge of cells migrating on surfaces coated with the LFA-1 ligand intercellular adhesion molecule-1 (ICAM-1). Knockout or knockdown of PTPN22 or expression of the autoimmune disease-associated PTPN22-R620W variant resulted in the enhanced phosphorylation of signaling molecules downstream of integrins. Superresolution imaging revealed that PTPN22-R620 (wild-type PTPN22) was present as large clusters in unstimulated T cells and that these disaggregated upon stimulation of LFA-1, enabling increased association of PTPN22 with its binding partners at the leading edge. The failure of PTPN22-R620W molecules to be retained at the leading edge led to increased LFA-1 clustering and integrin-mediated cell adhesion. Our data define a previously uncharacterized mechanism for fine-tuning integrin signaling in T cells, as well as a paradigm of autoimmunity in humans in which disease susceptibility is underpinned by inherited phosphatase mutations that perturb integrin function.
authors.affiliation: Academic Department of Rheumatology, Centre for Molecular and Cellular Biology of Inflammation, Faculty of Life Sciences and Medicine, King's College London, London SE1 1UL, U.K.
authors.forename: Garth L
authors.initials: GL
authors.lastname: Burn
authors.affiliation: Academic Department of Rheumatology, Centre for Molecular and Cellular Biology of Inflammation, Faculty of Life Sciences and Medicine, King's College London, London SE1 1UL, U.K.
authors.forename: Georgina H
authors.initials: GH
authors.lastname: Cornish
authors.affiliation: Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Potrzebowska
authors.affiliation: Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden.
authors.forename: Malin
authors.initials: M
authors.lastname: Samuelsson
authors.affiliation: Department of Physics and Randall Division of Cell and Molecular Biophysics, Faculty of Life Sciences and Medicine, King's College London, London SE1 1UL, U.K.
authors.forename: Juliette
authors.initials: J
authors.lastname: Griffié
authors.affiliation: Department of Physics and Randall Division of Cell and Molecular Biophysics, Faculty of Life Sciences and Medicine, King's College London, London SE1 1UL, U.K.
authors.forename: Sophie
authors.initials: S
authors.lastname: Minoughan
authors.affiliation: Academic Department of Rheumatology, Centre for Molecular and Cellular Biology of Inflammation, Faculty of Life Sciences and Medicine, King's College London, London SE1 1UL, U.K.
authors.forename: Mark
authors.initials: M
authors.lastname: Yates
authors.affiliation: Department of Physics and Randall Division of Cell and Molecular Biophysics, Faculty of Life Sciences and Medicine, King's College London, London SE1 1UL, U.K.
authors.forename: George
authors.initials: G
authors.lastname: Ashdown
authors.affiliation: Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Pernodet
authors.affiliation: Institute of Immunology, Infection and Inflammation, University of Glasgow, Glasgow G12 8TA, U.K.
authors.forename: Vicky L
authors.initials: VL
authors.lastname: Morrison
authors.affiliation: Academic Department of Rheumatology, Centre for Molecular and Cellular Biology of Inflammation, Faculty of Life Sciences and Medicine, King's College London, London SE1 1UL, U.K.
authors.forename: Cristina
authors.initials: C
authors.lastname: Sanchez-Blanco
authors.affiliation: Academic Department of Rheumatology, Centre for Molecular and Cellular Biology of Inflammation, Faculty of Life Sciences and Medicine, King's College London, London SE1 1UL, U.K.
authors.forename: Harriet
authors.initials: H
authors.lastname: Purvis
authors.affiliation: Academic Department of Rheumatology, Centre for Molecular and Cellular Biology of Inflammation, Faculty of Life Sciences and Medicine, King's College London, London SE1 1UL, U.K.
authors.forename: Fiona
authors.initials: F
authors.lastname: Clarke
authors.affiliation: Institute of Immunology and Infection Research, Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh EH9 3FL, U.K.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Brownlie
authors.affiliation: Department of Medical and Molecular Genetics, Faculty of Life Sciences and Medicine, King's College London, London SE1 9RT, U.K.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Vyse
authors.affiliation: Institute of Immunology and Infection Research, Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh EH9 3FL, U.K.
authors.forename: Rose
authors.initials: R
authors.lastname: Zamoyska
authors.affiliation: Department of Physics and Randall Division of Cell and Molecular Biophysics, Faculty of Life Sciences and Medicine, King's College London, London SE1 1UL, U.K.
authors.forename: Dylan M
authors.initials: DM
authors.lastname: Owen
authors.affiliation: Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden. andrew.cope@kcl.ac.uk lena_m.svensson@med.lu.se.
authors.forename: Lena M
authors.initials: LM
authors.lastname: Svensson
authors.affiliation: Academic Department of Rheumatology, Centre for Molecular and Cellular Biology of Inflammation, Faculty of Life Sciences and Medicine, King's College London, London SE1 1UL, U.K. andrew.cope@kcl.ac.uk lena_m.svensson@med.lu.se.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Cope
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D015551:Autoimmunity / Q000502:physiology*; D002448:Cell Adhesion / Q000235:genetics / Q000276:immunology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000276:immunology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D020125:Mutation, Missense; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology
chemical_list: C573420:ICAM1 protein, human; C090509:Icam1 protein, mouse; D016169:Lymphocyte Function-Associated Antigen-1; D018799:Intercellular Adhesion Molecule-1; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; C516766:Ptpn22 protein, mouse