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

Burn, G. L. et al. (2016) Superresolution imaging of the cytoplasmic phosphatase PTPN22 links integrin-mediated T cell adhesion with autoimmunity. Science Signaling, 9(448), ra99. (doi:10.1126/scisignal.aaf2195) (PMID:27703032)

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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 autoimmunity in humans in which disease susceptibility is underpinned by inherited phosphatase mutations that perturb integrin function.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Morrison, Dr Vicky
Authors: Burn, G. L., Cornish, G. H., Potrzebowska, K., Samuelsson, M., Griffie, J., Minoughan, S., Yates, M., Ashdown, G., Pernodet, N., Morrison, V. L., Sanchez-Blanco, C., Purvis, H., Clarke, F., Brownlie, R. J., Vyse, T. J., Zamoyska, R., Owen, D. M., Svensson, L. M., and Cope, A. P.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Science Signaling
Publisher:American Association for the Advancement of Science
ISSN:1945-0877
ISSN (Online):1937-9145
Copyright Holders:Copyright © 2016 American Association for the Advancement of Science
First Published:First published in Science Signaling 9(448):ra99
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
675351Integrin-mediated regulation of leukocytes in autoimmunity.Vicky MorrisonArthritis Research UK (ARUK)20848RI INFECTION IMMUNITY & INFLAMMATION