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

Research output: Contribution to journalArticle

Authors

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

Colleges, School and Institutes

External organisations

  • King's College London
  • University of Edinburgh
  • University of Glasgow
  • Lund University

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

Details

Original languageEnglish
JournalScience signaling
Volume9
Issue number448
Publication statusPublished - 4 Oct 2016