title: Induction of PP2A Bβ, a regulator of IL-2 deprivation-induced T-cell apoptosis, is deficient in systemic lupus erythematosus.
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 Bβ 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 Bβ were produced during IL-2 deprivation-induced apoptosis, whereas Fas ligation had no effect. Forced expression of the Bβ 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 Bβ in this autoimmune disease. We found that levels of PP2A Bβ 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 Bβ in a normal manner. We have identified a unique role for the phosphatase PP2A, particularly the holoenzyme formed by PP2A Bβ. Bβ 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 Bβ upon IL-2 deprivation results in apoptosis resistance and longer survival of autoreactive T cells, in a subset of SLE patients.
authors: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. crispin@bidmc.harvard.edu
authors: José C
authors: JC
authors: Crispín
authors: Sokratis A
authors: SA
authors: Apostolidis
authors: Melissa I
authors: MI
authors: Finnell
authors: George C
authors: GC
authors: Tsokos
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000276:immunology / Q000502:physiology; D016022:Case-Control Studies; D015536:Down-Regulation; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000378:metabolism*; D008180:Lupus Erythematosus, Systemic / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D015854:Up-Regulation; D055815:Young Adult
chemical_list: C508594:IL2 protein, human; D007376:Interleukin-2; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C505936:PPP2R2B protein, human; D054648:Protein Phosphatase 2