Department of Medicine, Beth Israel Deaconess Medical Center (BIDMC) and Harvard Medical School, Boston, Masschusetts, USA.
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
JCI Insight. 2020 Oct 2;5(19):138215. doi: 10.1172/jci.insight.138215.
Protein phosphatase 2A is a ubiquitously expressed serine/threonine phosphatase that comprises a scaffold, a catalytic, and multiple regulatory subunits and has been shown to be important in the expression of autoimmunity. We considered that a distinct subunit may account for the decreased production of IL-2 in people and mice with systemic autoimmunity. We show that the regulatory subunit PPP2R2D is increased in T cells from people with systemic lupus erythematosus and regulates IL-2 production. Mice lacking PPP2R2D only in T cells produce more IL-2 because the IL-2 gene and genes coding for IL-2-enhancing transcription factors remain open, while the levels of the enhancer phosphorylated CREB are high. Mice with T cell-specific PPP2R2D deficiency display less systemic autoimmunity when exposed to a TLR7 stimulator. While genes related to Treg function do not change in the absence of PPP2R2D, Tregs exhibit high suppressive function in vitro and in vivo. Because the ubiquitous expression of protein phosphatase 2A cannot permit systemic therapeutic manipulation, the identification of regulatory subunits able to control specific T cell functions opens the way for the development of novel, function-specific drugs.
蛋白磷酸酶 2A 是一种普遍表达的丝氨酸/苏氨酸磷酸酶，由支架、催化和多个调节亚基组成，已被证明在自身免疫的表达中很重要。我们认为，一个独特的亚基可能是导致系统性自身免疫患者和小鼠 IL-2 产量减少的原因。我们发现，系统性红斑狼疮患者的 T 细胞中，调节亚基 PPP2R2D 增加，并调节 IL-2 的产生。仅在 T 细胞中缺乏 PPP2R2D 的小鼠会产生更多的 IL-2，因为 IL-2 基因和编码增强 IL-2 转录因子的基因保持开放，而增强子磷酸化 CREB 的水平较高。当暴露于 TLR7 激动剂时，T 细胞特异性 PPP2R2D 缺乏的小鼠表现出较少的系统性自身免疫。虽然缺乏 PPP2R2D 时与 Treg 功能相关的基因没有改变，但 Treg 在体外和体内均表现出高抑制功能。由于蛋白磷酸酶 2A 的广泛表达不能允许系统性治疗干预，因此能够控制特定 T 细胞功能的调节亚基的鉴定为开发新型、功能特异性药物开辟了道路。
