Section of Immunology and Infection, Division of Applied Medicine, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, UK.
Eur J Immunol. 2013 May;43(5):1274-85. doi: 10.1002/eji.201242529. Epub 2013 Mar 6.
CTLA-4 is a crucial immune regulator that mediates both negative costimulation signals to T cells, and regulatory T (Treg)-cell extrinsic control of effector responses. Here we present evidence supporting a novel mechanism for this extrinsic suppression, executed by the alternatively spliced soluble CTLA-4 isoform (sCTLA-4). Analyses of human T cells in vitro show that sCTLA-4 secretion can be increased during responses, and has potent inhibitory properties, since isoform-specific blockade of its activity significantly increased Ag-driven proliferation and cytokine (IFN-γ, IL-17) secretion. Treg cells were demonstrated to be a prominent source of sCTLA-4, which contributed to suppression in vitro when their numbers were limiting. The soluble isoform was also produced by, and inhibited, murine T cells responding to Ag in vitro, and blockade of its activity in vivo protected against metastatic spread of melanoma in mice. We conclude that sCTLA-4 is an important immune regulator, responsible for at least some of the inhibitory effects previously ascribed to the membrane-bound isoform. These results suggest that the immune system exploits the different CTLA-4 isoforms for either intrinsic or extrinsic regulation of T-cell activity.
CTLA-4 是一种关键的免疫调节剂，介导 T 细胞的负共刺激信号和调节性 T（Treg）细胞对外周效应应答的控制。在这里，我们提供了支持这种外周抑制的新型机制的证据，该机制由 CTLA-4 的可替代剪接可溶性同种型（sCTLA-4）执行。对体外人 T 细胞的分析表明，sCTLA-4 的分泌可以在应答过程中增加，并且具有很强的抑制特性，因为其活性的同种型特异性阻断显著增加了 Ag 驱动的增殖和细胞因子（IFN-γ、IL-17）的分泌。Treg 细胞被证明是 sCTLA-4 的主要来源，当它们的数量有限时，sCTLA-4 在体外有助于抑制。可溶性同种型也由体外对 Ag 产生应答的小鼠 T 细胞产生，并抑制其活性，体内阻断其活性可防止黑色素瘤在小鼠中的转移扩散。我们得出结论，sCTLA-4 是一种重要的免疫调节剂，负责至少部分以前归因于膜结合同种型的抑制作用。这些结果表明，免疫系统利用不同的 CTLA-4 同种型来进行 T 细胞活性的内在或外在调节。
