Robson Neil C, Phillips David J, McAlpine Tristan, Shin Amanda, Svobodova Suzanne, Toy Tracey, Pillay Vinochani, Kirkpatrick Naomi, Zanker Damien, Wilson Kathy, Helling Imke, Wei Heng, Chen Weisan, Cebon Jonathan, Maraskovsky Eugene
Ludwig Institute for Cancer Research, Melbourne Centre for Clinical Sciences, Heidelberg, Victoria 3084, Australia.
Blood. 2008 Mar 1;111(5):2733-43. doi: 10.1182/blood-2007-03-080994. Epub 2007 Dec 21.
Activin-A is a transforming growth factor-beta (TGF-beta) superfamily member that plays a pivotal role in many developmental and reproductive processes. It is also involved in neuroprotection, apoptosis of tumor and some immune cells, wound healing, and cancer. Its role as an immune-regulating protein has not previously been described. Here we demonstrate for the first time that activin-A has potent autocrine effects on the capacity of human dendritic cells (DCs) to stimulate immune responses. Human monocyte-derived DCs (MoDCs) and the CD1c(+) and CD123(+) peripheral blood DC populations express both activin-A and the type I and II activin receptors. Furthermore, MoDCs and CD1c(+) myeloid DCs rapidly secrete high levels of activin-A after exposure to bacteria, specific toll-like receptor (TLR) ligands, or CD40 ligand (CD40L). Blocking autocrine activin-A signaling in DCs using its antagonist, follistatin, enhanced DC cytokine (IL-6, IL-10, IL-12p70, and tumor necrosis factor-alpha [TNF-alpha]) and chemokine (IL-8, IP-10, RANTES, and MCP-1) production during CD40L stimulation, but not TLR-4 ligation. Moreover, antagonizing DC-derived activin-A resulted in significantly enhanced expansion of viral antigen-specific effector CD8(+) T cells. These findings establish an immune-regulatory role for activin-A in DCs, highlighting the potential of antagonizing activin-A signaling in vivo to enhance vaccine immunogenicity.
激活素A是转化生长因子-β（TGF-β）超家族成员，在许多发育和生殖过程中起关键作用。它还参与神经保护、肿瘤及某些免疫细胞的凋亡、伤口愈合和癌症。此前尚未描述其作为免疫调节蛋白的作用。在此，我们首次证明激活素A对人树突状细胞（DC）刺激免疫反应的能力具有强大的自分泌作用。人单核细胞衍生的DC（MoDC）以及CD1c(+)和CD123(+)外周血DC群体均表达激活素A以及I型和II型激活素受体。此外，MoDC和CD1c(+)髓样DC在暴露于细菌、特异性Toll样受体（TLR）配体或CD40配体（CD40L）后会迅速分泌高水平的激活素A。使用其拮抗剂卵泡抑素阻断DC中的自分泌激活素A信号，可增强CD40L刺激期间DC细胞因子（IL-6、IL-10、IL-12p70和肿瘤坏死因子-α [TNF-α]）和趋化因子（IL-8、IP-10、RANTES和MCP-1）的产生，但不影响TLR-4连接。此外，拮抗DC衍生的激活素A可显著增强病毒抗原特异性效应CD8(+) T细胞的扩增。这些发现确立了激活素A在DC中的免疫调节作用，突出了在体内拮抗激活素A信号以增强疫苗免疫原性的潜力。
