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Superresolution imaging of the cytoplasmic phosphatase PTPN22 links integrin-mediated T cell adhesion with autoimmunity

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Author

  • Garth L. Burn
  • Georgina H. Cornish
  • Kasia Potrzebowska
  • Malin Samuelsson
  • Juliette Griffié
  • Sophie Minoughan
  • Mark Yates
  • George Ashdown
  • Nicolas Pernodet
  • Vicky L. Morrison
  • Cristina Sanchez-Blanco
  • Harriet Purvis
  • Fiona Clarke
  • Rebecca J. Brownlie
  • Timothy J. Vyse
  • Rose Zamoyska
  • Dylan M. Owen
  • Lena M. Svensson
  • Andrew P. Cope
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Summary, in English

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 auto-immunity in humans in which disease susceptibility is underpinned by inherited phosphatase mutations that perturb integrin function. 2016

Department/s

  • Leukocyte Migration

Publishing year

2016-10-04

Language

English

Publication/Series

Science Signaling

Volume

9

Issue

448

Document type

Journal article

Publisher

American Association for the Advancement of Science (AAAS)

Topic

  • Cell and Molecular Biology

Status

Published

Research group

  • Leukocyte Migration

ISBN/ISSN/Other

  • ISSN: 1945-0877