Design of soluble recombinant T cell receptors for antigen targeting and T cell inhibition
Design of soluble recombinant T cell receptors for antigen targeting and T cell inhibition
复制标题
DOI：
10.1074/jbc.m409427200
复制
发表时间：
2005-01-21
影响因子：
4.8
通讯作者：
Sewell, AK
中科院分区：
文献类型：
--
作者：
Laugel, B;Boulter, JM;Sewell, AK
使用重组 T 细胞受体 (TCR) 进行靶向治疗干预受到 TCR 与肽主要组织相容性复合物配体相互作用的天然低亲和力的阻碍。在这里，我们使用多聚体形式的可溶性异二聚字母 TCR 来特异性检测同源肽脉冲的靶细胞，区分细胞表面抗原展示的数量变化，识别病毒感染的细胞，抑制抗原特异性细胞毒性 T 淋巴细胞活化，以及识别交叉反应肽。值得注意的是，A6 TCR 对免疫显性 HLA A2 限制性人 T 细胞白血病病毒 1 型 Tax(11-19) 表位具有特异性，该表位与 HLA A2-HuD(87-95)（通过表面等离子共振得出的 K-D 120 muM）结合，该表位是副肿瘤性神经退行性疾病抗 Hu 综合征中的致病抗原。产生了突变体 A6 TCR，其对同源抗原的亲和力显着增加 (K-D 2.5 nM)，但交叉反应性没有增强；即使作为单体分子，该 TCR 也表现出强大的生物活性。这些数据提供了对 TCR 库选择的见解，并描绘了体外选择性修饰 TCR 的框架，从而可以实现体内特定的治疗干预。
The use of recombinant T cell receptors (TCRs) to target therapeutic interventions has been hindered by the naturally low affinity of TCR interactions with peptide major histocompatibility complex ligands. Here, we use multimeric forms of soluble heterodimeric alphabeta TCRs for specific detection of target cells pulsed with cognate peptide, discrimination of quantitative changes in antigen display at the cell surface, identification of virus-infected cells, inhibition of antigen-specific cytotoxic T lymphocyte activation, and identification of cross-reactive peptides. Notably, the A6 TCR specific for the immunodominant HLA A2-restricted human T cell leukemia virus type 1 Tax(11-19) epitope bound to HLA A2-HuD(87-95) (K-D 120 muM by surface plasmon resonance), an epitope implicated as a causal antigen in the paraneoplastic neurological degenerative disorder anti-Hu syndrome. A mutant A6 TCR that exhibited dramatically increased affinity for cognate antigen (K-D 2.5 nM) without enhanced cross-reactivity was generated; this TCR demonstrated potent biological activity even as a monomeric molecule. These data provide insights into TCR repertoire selection and delineate a framework for the selective modification of TCRs in vitro that could enable specific therapeutic intervention in vivo.