Induction of PP2A Bß, a regulator of IL-2 deprivation-induced T-cell apoptosis, is deficient in systemic lupus erythematosus.
Proc Natl Acad Sci U S A
; 108(30): 12443-8, 2011 Jul 26.
Article
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| MEDLINE
| ID: mdl-21746932
ABSTRACT
The activity and substrate specificity of the ubiquitously expressed phosphatase PP2A is determined by the type of regulatory (B) subunit that couples to the catalytic/scaffold core of the enzyme. We determined that the Bß subunit (PPP2R2B) is expressed in resting T cells, its transcription is down-regulated during T-cell activation, and up-regulated in conditions of low IL-2. Specifically, high levels of PP2A Bß were produced during IL-2 deprivation-induced apoptosis, whereas Fas ligation had no effect. Forced expression of the Bß subunit in primary human T cells was sufficient to induce apoptosis, whereas silencing using siRNA protected activated T cells from IL-2 withdrawal-induced cell death. Because T-cell apoptosis is known to be altered in T cells from patients with systemic lupus erythematosus, we analyzed the regulation of PP2A Bß in this autoimmune disease. We found that levels of PP2A Bß did not increase upon IL-2 deprivation in 50% of the patients. Remarkably, this defect was accompanied by resistance to apoptosis. Importantly, kinetics of cell death were normal in cells of patients that up-regulated PP2A Bß in a normal manner. We have identified a unique role for the phosphatase PP2A, particularly the holoenzyme formed by PP2A Bß. Bß appears to trigger apoptosis of T cells in the absence of IL-2 and probably contributes to the termination of a no-longer-needed immune response. We propose that defective production of PP2A Bß upon IL-2 deprivation results in apoptosis resistance and longer survival of autoreactive T cells, in a subset of SLE patients.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Linfocitos T
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Interleucina-2
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Proteína Fosfatasa 2
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Lupus Eritematoso Sistémico
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Proteínas del Tejido Nervioso
Tipo de estudio:
Observational_studies
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Prognostic_studies
Límite:
Adult
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Año:
2011
Tipo del documento:
Article
País de afiliación:
Estados Unidos