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KINETIC ANALYSIS OF ANTIGEN-PRESENTATION OF HIV-INFECTED CELLS USING SOLUBLE T CELL RECEPTORS

使用可溶性 T 细胞受体对 HIV 感染细胞的抗原呈递进行动力学分析

基本信息

批准号：
13670300
负责人：
UENO Takamasa
金额：
$ 2.3万
依托单位：
KUMAMOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670300/
关键词：
T CELL RECEPTOR ANTIGEN PRESENTATION HLA CYTOTOXIC T LYMPHOCYTE HIV CELLULAR IMMUNITY RECOMBINANT PROTEIN SURFACE PLASMON RESONANCE 細胞傷害性T細胞組換え蛋白質

项目摘要

A dual specific human CTL clone harboring one β and two in-frame α transcripts of T cell receptor (TCR) was previously reported to recognize an HIV Pol-derived nonapeptide (IPLTEEAEL) endogenously presented by both syngeneic HLA-B*3501 and HLA-B*5101. In the present study, a retrovirus-mediated TCR transfer of individual α and β chains to TCR-negative hybridoma showed that Vα12.1 TCR in complex with Vβ5.6 were responsible for the peptide-specific response in the context of both HLA-B*3501 and HLA-B*5101, confirming single TCR-mediated dual specificity. The second TCR-α chain was not somehow expressed on the cell surface. Remarkably, the Vα12/Vβ5.6 TCR also recognized the same peptide presented by allogeneic HLA class I molecules that share the similar peptide-binding motifs, such as HLA-B*5301 and HLA-B*0702. The sensitivity of peptide recognition by the Vα12/Vβ5.6 TCR appeared to be comparable when the peptide was presented by syngeneic and allogeneic HLA class I molecules, with changes in T cell responsiveness caused largely by peptide binding capacity. Moreover, the CTL clone bearing Vα12/Vβ5.6 TCR showed substantial cytolytic activity against the peptide-loaded cells expressing HLA-B*3501, HLA-B*5101, HLA-B*5301, or HLA-B*0702, providing further evidence that a single TCR complex can recognize the same peptide presented by a broad range of HLA class I molecules. A TCR with fine specificity for an HIV antigen but broad specificity to multiple HLA molecules may provide an advantage to the generation of allorestricted, peptide-specific T cells, and thus could be a potent candidate for immunotherapy against HIV infection.

先前报道，含有 T 细胞受体 (TCR) 的一个 β 转录物和两个框内 α 转录物的双特异性人类 CTL 克隆能够识别由同源 HLA-B*3501 和 HLA-B*5101 内源呈递的 HIV Pol 衍生九肽 (IPLTEEAEL)。在本研究中，逆转录病毒介导的单个 α 和 β 链向 TCR 阴性杂交瘤的 TCR 转移表明，与 Vβ5.6 复合的 Vα12.1 TCR 负责 HLA-B*3501 和 HLA-B*5101 背景下的肽特异性反应，证实了单一 TCR 介导的双重特异性。第二条 TCR-α 链并未以某种方式在细胞表面表达。值得注意的是，Vα12/Vβ5.6 TCR 还识别同种异体 HLA I 类分子呈现的相同肽，这些分子具有相似的肽结合基序，例如 HLA-B*5301 和 HLA-B*0702。当肽由同源和同种异体 HLA I 类分子呈递时，Vα12/Vβ5.6 TCR 识别肽的敏感性似乎相当，T 细胞反应性的变化主要由肽结合能力引起。此外，携带 Vα12/Vβ5.6 TCR 的 CTL 克隆对表达 HLA-B*3501、HLA-B*5101、HLA-B*5301 或 HLA-B*0702 的肽负载细胞表现出显着的细胞溶解活性，进一步证明单个 TCR 复合物可以识别由广泛的 HLA I 类分子呈递的相同肽。对 HIV 抗原具有良好特异性但对多个 HLA 分子具有广泛特异性的 TCR 可能为同种异体限制性肽特异性 T 细胞的生成提供优势，因此可能成为针对 HIV 感染的免疫疗法的有力候选者。