Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Huddinge, Sweden.
J Leukoc Biol. 2021 Oct;110(4):617-628. doi: 10.1002/JLB.3HI0720-431R. Epub 2021 May 24.
Protective cytotoxic and proinflammatory cytokine responses by NK cells impact the outcome of infections by Toxoplasma gondii, a common parasite in humans and other vertebrates. However, T. gondii can also sequester within NK cells and downmodulate their effector functions. Recently, the implication of GABA signaling in infection and inflammation-related responses of mononuclear phagocytes and T cells has become evident. Yet, the role of GABAergic signaling in NK cells has remained unknown. Here, we report that human and murine NK cells synthesize and secrete GABA in response to infection challenge. Parasitized NK cells secreted GABA, whereas activation stimuli, such as IL-12/IL-18 or parasite lysates, failed to induce GABA secretion. GABA secretion by NK cells was associated to a transcriptional up-regulation of GABA synthesis enzymes (glutamate decarboxylases [GAD65/67]) and was abrogated by GAD inhibition. Further, NK cells expressed GABA-A receptor subunits and GABA signaling regulators, with transcriptional modulations taking place upon challenge with T. gondii. Exogenous GABA and GABA-containing supernatants from parasitized dendritic cells (DCs) impacted NK cell function by reducing the degranulation and cytotoxicity of NK cells. Conversely, GABA-containing supernatants from NK cells enhanced the migratory responses of parasitized DCs. This enhanced DC migration was abolished by GABA-A receptor antagonism or GAD inhibition and was reconstituted by exogenous GABA. Jointly, the data show that NK cells are GABAergic cells and that GABA hampers NK cell cytotoxicity in vitro. We hypothesize that GABA secreted by parasitized immune cells modulates the immune responses to T. gondii infection.
NK 细胞的保护性细胞毒性和促炎细胞因子反应影响了人类和其他脊椎动物常见寄生虫弓形虫感染的结果。然而，弓形虫也可以在 NK 细胞内隔离并下调其效应功能。最近，GABA 信号在单核吞噬细胞和 T 细胞的感染和炎症相关反应中的作用已经很明显。然而，GABA 能信号在 NK 细胞中的作用仍然未知。在这里，我们报告人类和鼠 NK 细胞在受到感染挑战时会合成和分泌 GABA。被寄生虫感染的 NK 细胞分泌 GABA，而激活刺激物，如 IL-12/IL-18 或寄生虫裂解物，不能诱导 GABA 分泌。NK 细胞分泌 GABA 与 GABA 合成酶（谷氨酸脱羧酶[GAD65/67]）的转录上调有关，并被 GAD 抑制所阻断。此外，NK 细胞表达 GABA-A 受体亚基和 GABA 信号调节剂，在受到弓形虫挑战时会发生转录调节。外源性 GABA 和含有 GABA 的寄生虫树突状细胞（DC）上清液通过减少 NK 细胞的脱颗粒和细胞毒性来影响 NK 细胞功能。相反，含有 GABA 的 NK 细胞上清液增强了被寄生虫感染的 DC 的迁移反应。这种增强的 DC 迁移被 GABA-A 受体拮抗剂或 GAD 抑制所阻断，并通过外源性 GABA 得到重建。总的来说，这些数据表明 NK 细胞是 GABA 能细胞，GABA 可在体外抑制 NK 细胞的细胞毒性。我们假设被寄生虫感染的免疫细胞分泌的 GABA 可调节对弓形虫感染的免疫反应。
