EXPRESSION OF IMMUNOGLOBULIN-T-CELL RECEPTOR CHIMERIC MOLECULES AS FUNCTIONAL RECEPTORS WITH ANTIBODY-TYPE SPECIFICITY
EXPRESSION OF IMMUNOGLOBULIN-T-CELL RECEPTOR CHIMERIC MOLECULES AS FUNCTIONAL RECEPTORS WITH ANTIBODY-TYPE SPECIFICITY
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DOI：
10.1073/pnas.86.24.10024
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发表时间：
1989-12-01
影响因子：
11.1
通讯作者：
ESHHAR, Z
中科院分区：
文献类型：
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作者：
GROSS, G;WAKS, T;ESHHAR, Z
为了以非主要组织相容性复合体 (MHC) 限制的方式随意设计和指导 T 细胞的特异性，我们生成并表达了嵌合 T 细胞受体 (TcR) 基因，该基因由与抗体可变 (V) 域融合的 TcR 恒定 (C) 域组成。已经构建了基因组表达载体，其包含编码抗2,4,6-三硝基苯基(TNP)抗体(SP6)的重链(VH)和轻链(VL)的V区结构域的重排基因片段，其剪接至.α抗体的任一C区基因片段。或.beta。 TcR 链。转染细胞毒性 T 细胞杂交瘤后，检测到功能性 TcR 的表达。嵌合 TcR 表现出 Sp6 抗 TNP 抗体的独特位，并赋予 T 细胞对半抗原 TNP 的非 MHC 限制性反应。转染子跨越菌株和物种障碍，特异性地杀死并产生白细胞介素 2，以响应携带 TNP 的靶细胞。此外，此类转染子对固定的 TNP-蛋白缀合物有反应，绕过了细胞加工和呈递的需要。在所采用的特定系统中，TNP 结合位点和 Sp6 独特位几乎完全位于 VH 链区域。因此，将仅含有与C.alpha融合的VHSp6的TcR基因引入T细胞中。或C.beta。足以表达功能性表面受体。显然，VHC.alpha。或VHC.beta。嵌合链可以与内源性.β配对。或.alpha。受体 T 细胞链形成功能性 α..β。异二聚体受体。因此，这种嵌合受体为T细胞提供了类似抗体的特异性，并且能够有效地传递T细胞激活和执行其效应功能的信号。
To design and direct at will the specificity of T cells in a non-major histocompatibility complex (MHC)-restricted manner, we have generated and expressed chimeric T-cells receptor (TcR) genes composed of the TcR constant (C) domains fused to the antibody''s variable (V) domains. Genomic expression vectors have been constructed containing the rearranged gene segments coding for the V region domains of the heavy (VH) and light (VL) chains of an anti-2,4,6-trinitrophenyl (TNP) antibody (SP6) spliced to either one of the C-region gene segments of the .alpha. or .beta. TcR chains. Following transfection into a cytotoxic T-cell hybridoma, expression of a functional TcR was detected. The chimeric TcR exhibited the idiotope of the Sp6 anti-TNP antibody and endowed the T cells with a non MHC-restricted response to the hapten TNP. The transfectants specifically killed and produced interleukin 2 in response to TNP-bearing target cells across strain and species barriers. Moreover, such transfectants responsed to immobilized TNP-protein conjugates, bypassing the need for cellular processing and presentation. In the particular system employed, both the TNP-binding site and the Sp6 idiotope reside almost exclusively in the VH chain region. Hence, introduction into T cells of TcR genes containing only th VHSp6 fused to either the C.alpha. or C.beta. was sufficient for the expression of a functional surface receptor. Apparently, the VHC.alpha. or VHC.beta. chimeric chains can pair with the endogenous .beta. or .alpha. chains of the recipient T cell to form a functional .alpha..beta. heterodimeric receptor. Thus, this chimeric receptor provides the T cell with an antibody-like specificity and is able to effectively transmit the signal for T-cell activation and execution of its effector function.