Meidan Esra, Li Hao, Pan Wenliang, Kono Michihito, Yu Shuilian, Kyttaris Vasileios C, Ioannidis Christina, Rodriguez Rodriguez Noe, Crispin Jose C, Apostolidis Sokratis A, Lee Pui, Manis John, Sharabi Amir, Tsokos Maria G, Tsokos George C
Department of Medicine, Beth Israel Deaconess Medical Center (BIDMC), Boston, Massachusetts, USA.
Division of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA.
JCI Insight. 2020 Mar 12;5(5):130655. doi: 10.1172/jci.insight.130655.
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.
蛋白磷酸酶2A（PP2A）是一种丝氨酸/苏氨酸磷酸酶，已被证明可控制T细胞功能。我们发现，体外激活的B细胞以及来自各种狼疮易感小鼠和系统性红斑狼疮患者的B细胞，其PP2A活性均有所增加。为了解PP2A对B细胞功能的作用，我们构建了Cd19CrePpp2r1afl/fl（flox/flox）小鼠，该小鼠仅在B细胞中缺乏功能性PP2A。Flox/flox小鼠的生发中心自发形成减少，对T细胞依赖性和T细胞非依赖性抗原的反应降低，而其B细胞在体外与IL-4共同存在时，对抗CD40抗体或CpG的刺激反应较差。转录组和代谢组研究表明，PP2A缺陷型B细胞中的烟酰胺腺嘌呤二核苷酸（NAD）以及嘌呤/嘧啶代谢发生改变，嘌呤核苷磷酸化酶的表达增加。我们的结果表明，PP2A是最佳B细胞功能所必需的，并且可能导致系统性自身免疫中B细胞活性增加。
