McHugh R S, Ahmed S N, Wang Y C, Sell K W, Selvaraj P
Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322, USA.
Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):8059-63. doi: 10.1073/pnas.92.17.8059.
To generate a potent cell-mediated immune response, at least two signals are required by T cells. One is engagement of the T-cell receptor with peptide-bearing major histocompatibility complex molecules. The other signal can be delivered by various molecules on the antigen-presenting cell, such as B7-1 (CD80). Many tumor cells escape immune recognition by failing to express these costimulatory molecules. Transfection of the B7 gene into some murine tumor cells allows for immune recognition and subsequent rejection of the parental tumor. We have studied an alternative approach for the introduction of B7-1 onto the surface of tumor cells. This method involves purified glycosyl-phosphatidylinositol (GPI)-anchored proteins which can spontaneously incorporate their lipid tail into cell membranes. We have created and purified a GPI-anchored B7-1 molecule (called GPI-B7) which is able to bind its cognate ligand, CD28, and incorporate itself into tumor cell membranes after a short incubation. Tumor cells that have been reconstituted with GPI-B7 can provide the costimulatory signal needed to stimulate T cells. These findings suggest an approach for the introduction of new proteins onto cell membranes to create an effective tumor vaccine for potential use in human immunotherapy.
为了产生有效的细胞介导免疫反应，T细胞至少需要两种信号。一种是T细胞受体与携带肽的主要组织相容性复合体分子的结合。另一种信号可由抗原呈递细胞上的各种分子传递，如B7-1（CD80）。许多肿瘤细胞因未能表达这些共刺激分子而逃避免疫识别。将B7基因转染到一些小鼠肿瘤细胞中可实现免疫识别并随后排斥亲代肿瘤。我们研究了一种将B7-1引入肿瘤细胞表面的替代方法。该方法涉及纯化的糖基磷脂酰肌醇（GPI）锚定蛋白，其能够将脂质尾巴自发地整合到细胞膜中。我们已经制备并纯化了一种GPI锚定的B7-1分子（称为GPI-B7），它能够结合其同源配体CD28，并在短暂孵育后将自身整合到细胞膜中。用GPI-B7重构的肿瘤细胞可以提供刺激T细胞所需的共刺激信号。这些发现提示了一种将新蛋白质引入细胞膜以创建一种可用于人类免疫治疗的有效肿瘤疫苗的方法。
