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

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, Fiona Clarke, Rebecca J. Brownlie, Timothy J. Vyse, Rose Zamoyska, Dylan M. Owen, Lena M. Svensson*, Andrew P. Cope

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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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

Original languageEnglish
Article numberra99
JournalScience Signaling
Volume9
Issue number448
Early online date4 Oct 2016
DOIs
Publication statusPublished - 4 Oct 2016

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