Department of Neuroscience, Section Medical Physiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Department of Pathology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Glia. 2018 Dec;66(12):2645-2658. doi: 10.1002/glia.23517. Epub 2018 Oct 11.
V-type immunoglobulin domain-containing suppressor of T-cell activation (VISTA) is a negative checkpoint regulator (NCR) involved in inhibition of T cell-mediated immunity. Expression changes of other NCRs (PD-1, PD-L1/L2, CTLA-4) during inflammation of the central nervous system (CNS) were previously demonstrated, but VISTA expression in the CNS has not yet been explored. Here, we report that in the human and mouse CNS, VISTA is most abundantly expressed by microglia, and to lower levels by endothelial cells. Upon TLR stimulation, VISTA expression was reduced in primary neonatal mouse and adult rhesus macaque microglia in vitro. In mice, microglial VISTA expression was reduced after lipopolysaccharide (LPS) injection, during experimental autoimmune encephalomyelitis (EAE), and in the accelerated aging Ercc1 mouse model. After LPS injection, decreased VISTA expression in mouse microglia was accompanied by decreased acetylation of lysine residue 27 in histone 3 in both its promoter and enhancer region. ATAC-sequencing indicated a potential regulation of VISTA expression by Pu.1 and Mafb, two transcription factors crucial for microglia function. Finally, our data suggested that VISTA expression was decreased in microglia in multiple sclerosis lesion tissue, whereas it was increased in Alzheimer's disease patients. This study is the first to demonstrate that in the CNS, VISTA is expressed by microglia, and that VISTA is differentially expressed in CNS pathologies.
V 型免疫球蛋白结构域包含的 T 细胞激活抑制因子（VISTA）是一种负性检查点调节剂（NCR），参与抑制 T 细胞介导的免疫。此前已经证明，在中枢神经系统（CNS）炎症期间，其他 NCR（PD-1、PD-L1/L2、CTLA-4）的表达发生变化，但 CNS 中的 VISTA 表达尚未得到探索。在这里，我们报告在人和小鼠的 CNS 中，VISTA 主要由小胶质细胞表达，内皮细胞表达水平较低。在体外，TLR 刺激后，原代新生小鼠和成年恒河猴小胶质细胞中的 VISTA 表达减少。在小鼠中，脂多糖（LPS）注射后、实验性自身免疫性脑脊髓炎（EAE）期间和加速衰老的 Ercc1 小鼠模型中，小胶质细胞的 VISTA 表达减少。LPS 注射后，小鼠小胶质细胞中 VISTA 表达的减少伴随着组蛋白 3 启动子和增强子区域赖氨酸残基 27 乙酰化的减少。ATAC 测序表明，Pu.1 和 Mafb 这两种对小胶质细胞功能至关重要的转录因子可能对 VISTA 的表达进行调控。最后，我们的数据表明，多发性硬化病变组织中的小胶质细胞中 VISTA 的表达减少，而阿尔茨海默病患者中 VISTA 的表达增加。这项研究首次证明，在 CNS 中，VISTA 由小胶质细胞表达，并且 VISTA 在 CNS 病理中表达不同。
