Department of Microbiology and Immunology, Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, NH 03766, USA.
J Exp Med. 2011 Mar 14;208(3):577-92. doi: 10.1084/jem.20100619. Epub 2011 Mar 7.
The immunoglobulin (Ig) superfamily consists of many critical immune regulators, including the B7 family ligands and receptors. In this study, we identify a novel and structurally distinct Ig superfamily inhibitory ligand, whose extracellular domain bears homology to the B7 family ligand PD-L1. This molecule is designated V-domain Ig suppressor of T cell activation (VISTA). VISTA is primarily expressed on hematopoietic cells, and VISTA expression is highly regulated on myeloid antigen-presenting cells (APCs) and T cells. A soluble VISTA-Ig fusion protein or VISTA expression on APCs inhibits T cell proliferation and cytokine production in vitro. A VISTA-specific monoclonal antibody interferes with VISTA-induced suppression of T cell responses by VISTA-expressing APCs in vitro. Furthermore, anti-VISTA treatment exacerbates the development of the T cell-mediated autoimmune disease experimental autoimmune encephalomyelitis in mice. Finally, VISTA overexpression on tumor cells interferes with protective antitumor immunity in vivo in mice. These findings show that VISTA, a novel immunoregulatory molecule, has functional activities that are nonredundant with other Ig superfamily members and may play a role in the development of autoimmunity and immune surveillance in cancer.
免疫球蛋白（Ig）超家族包含许多关键的免疫调节剂，包括 B7 家族配体和受体。在这项研究中，我们鉴定了一种新型的、结构独特的 Ig 超家族抑制性配体，其细胞外结构域与 B7 家族配体 PD-L1 具有同源性。该分子被命名为 T 细胞活化的 V 结构域 Ig 抑制物（VISTA）。VISTA 主要在造血细胞上表达，其在髓系抗原呈递细胞（APC）和 T 细胞上的表达受到高度调控。VISTA-Ig 融合蛋白或 APC 上的 VISTA 表达可在体外抑制 T 细胞增殖和细胞因子产生。VISTA 特异性单克隆抗体可干扰 VISTA 表达的 APC 体外诱导的 T 细胞反应的抑制作用。此外，抗 VISTA 治疗可加重小鼠 T 细胞介导的自身免疫性疾病实验性自身免疫性脑脊髓炎的发展。最后，肿瘤细胞上的 VISTA 过表达可干扰小鼠体内保护性抗肿瘤免疫。这些发现表明，VISTA 作为一种新型的免疫调节分子，具有与其他 Ig 超家族成员不同的功能活性，可能在自身免疫和癌症免疫监视的发展中发挥作用。
