Serine/threonine phosphatase PP2A is essential for optimal B cell function
Esra Meidan, Hao Li, Wenliang Pan, Michihito Kono, Shuilian Yu, Vasileios C. Kyttaris, Christina Ioannidis, Noe Rodriguez Rodriguez, Jose C. Crispin, Sokratis A. Apostolidis, Pui Lee, John Manis, Amir Sharabi, Maria G. Tsokos, George C. Tsokos
Esra Meidan, Hao Li, Wenliang Pan, Michihito Kono, Shuilian Yu, Vasileios C. Kyttaris, Christina Ioannidis, Noe Rodriguez Rodriguez, Jose C. Crispin, Sokratis A. Apostolidis, Pui Lee, John Manis, Amir Sharabi, Maria G. Tsokos, George C. Tsokos
View: Text | PDF
Research Article Immunology

Serine/threonine phosphatase PP2A is essential for optimal B cell function

Abstract

Protein phosphatase 2A (PP2A), a serine/threonine phosphatase, has been shown to control T cell function. We found that in vitro–activated B cells and B cells from various lupus-prone mice and patients with systemic lupus erythematosus display increased PP2A activity. To understand the contribution of PP2A to B cell function, we generated a Cd19CrePpp2r1afl/fl (flox/flox) mouse which lacks functional PP2A only in B cells. Flox/flox mice displayed reduced spontaneous germinal center formation and decreased responses to T cell-dependent and T-independent antigens, while their B cells responded poorly in vitro to stimulation with an anti-CD40 antibody or CpG in the presence of IL-4. Transcriptome and metabolome studies revealed altered nicotinamide adenine dinucleotide (NAD) and purine/pyrimidine metabolism and increased expression of purine nucleoside phosphorylase in PP2A-deficient B cells. Our results demonstrate that PP2A is required for optimal B cell function and may contribute to increased B cell activity in systemic autoimmunity.

Authors

Esra Meidan, Hao Li, Wenliang Pan, Michihito Kono, Shuilian Yu, Vasileios C. Kyttaris, Christina Ioannidis, Noe Rodriguez Rodriguez, Jose C. Crispin, Sokratis A. Apostolidis, Pui Lee, John Manis, Amir Sharabi, Maria G. Tsokos, George C. Tsokos

×

Figure 4

PP2A expression in B cells for disease development in mice after injection of pristine.

Options: View larger image (or click on image) Download as PowerPoint
PP2A expression in B cells for disease development in mice after injecti...
(A and B) Indicated mice were challenged i.p. with 0.5 mL pristine. (A) Blot graph shows ANA antibody levels in the serum of flox/flox and control mice 1 month after pristine challenge (n = 6 mice per group). (B) Immunofluorescence image analysis to detect IgG deposition in the kidneys of flox/flox and control mice 6 months after pristine challenge (n = 6 mice per group). (C) Western blot analysis on pSTAT3 and total STAT3 expression in B cells with PP2A deficiency. Quantification of Western blots. (D–F) Human B cells were enriched from peripheral blood mononuclear cells (PBMC) using MACS cell separation kits. (D) Western blot analysis to detect PP2Aa and PP2Ac in human B cells treated with control or PP2Aa siRNA. Quantification of Western blot densities. (E) Flow cytometry analysis on pSTAT3 induction during B cell activation in the absence of PP2Aa. (F) Immunofluorescence image analysis on pSTAT3 expression during B cell activation in the absence of PP2Aa. Original magnification ×63. Paired t test, *P < 0.05, ***P < 0.005, mean ± SEM.