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
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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

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Figure 3

PP2A is critical for B cell activation, differentiation, and Ig production in vivo.

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PP2A is critical for B cell activation, differentiation, and Ig producti...
(A) Dot plots show the percentages of spontaneous germinal center B cells (GC-CD19+FAS+PNA+) and T follicular helper cells (Tfh-CD4+CXCR5hiPD1hi) in spleens of the indicated 24-week-old mice (n = 6 mice per group for 2 independent experiments). (B and C) Mice were immunized i.p. with 0.2 mL/mouse SRBC. (B) IHC staining of frozen spleen sections of the indicated mice (n = 3 mice per group in 2 independent experiments). Bar graphs show the quantification (percentage) of follicles with germinal centers in total splenic follicles from the indicated mice (n = 3 mice per group in 2 independent experiments). (C) Flow cytometry analysis (%) of germinal center B cells (GC-CD19+FAS+PNA+), T follicular helper cells (Tfh-CD4+CXCR5hiPD1hi), and IgG plasma cells (PC-CD19+IgG+CD138+) in the spleens of the indicated mice after SRBC immunization. (D and E) Indicated mice were i.p. immunized with 100 μg/mouse NP-Ficoll for 5 days or 100 μg/mouse NP-CGG in 5% alum for 14 days. (D) ELISA analysis for high affinity (NP-7) or low affinity (NP-41) for NP antigen-specific IgM in the serum of 12-week-old flox/flox mice compared with control mice 5 days after immunization with T-independent antigen NP-Ficoll (n = 3 per group in 2 independent experiments). (E) ELISA analysis of high affinity (NP-7) or all affinity (NP-41) NP antigen-specific IgG in the serum of 12-week-old flox/flox mice compared with control mice 14 days after immunization with T-dependent antigen NP-CGG (n = 3 per group in 2 independent experiments). Paired t test, **P < 0.01, ***P < 0.05, mean ± SEM.