Superresolution imaging of the cytoplasmic phosphatase PTPN22 links integrin-mediated T cell adhesion with autoimmunity.
Sci Signal
; 9(448): ra99, 2016 10 04.
Article
en En
| MEDLINE
| ID: mdl-27703032
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.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Linfocitos T
/
Autoinmunidad
/
Molécula 1 de Adhesión Intercelular
/
Proteína Tirosina Fosfatasa no Receptora Tipo 22
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Sci Signal
Asunto de la revista:
CIENCIA
/
FISIOLOGIA
Año:
2016
Tipo del documento:
Article
País de afiliación:
Reino Unido