TCR-Ligand koff Rate Correlates with the Protective Capacity of Antigen-Specific CD8+ T Cells for Adoptive Transfer
TCR-Ligand koff Rate Correlates with the Protective Capacity of Antigen-Specific CD8+ T Cells for Adoptive Transfer
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DOI：
10.1126/scitranslmed.3005958
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发表时间：
2013-07-03
影响因子：
17.1
通讯作者：
Busch, Dirk H.
中科院分区：
文献类型：
--
作者：
Nauerth, Magdalena;Weissrich, Bianca;Busch, Dirk H.
免疫疗法是治疗慢性感染和癌症的一种有前途的治疗方法。对于其同源配体，在一定范围内的高亲合力的T细胞被认为是最有效的。T细胞受体（TCR）转移实验表明，亲合力的主要部分在TCR的结构内是硬连线的。不幸的是，在活T细胞上快速测量TCR的结构亲合力是困难的。我们开发了一种技术，其中真正的单体肽-主要组织相容性复合物（pMHC）分子结合到表面表达的TCR的解离（k（off）率）可以通过实时显微镜以高度可靠的方式进行监测。该方法对不同的人巨细胞病毒（CMV）特异性T细胞群体的首次评价显示了k（off）率的意外差异。CMV特异性T细胞目前正在临床试验中评估过继免疫治疗的功效;因此，koff率的测定可以指导最有效供体细胞的选择。事实上，在两种不同的鼠感染模型中，我们证明了具有较低k（off）速率的T细胞群体比具有快速k（off）速率的群体具有更好的保护作用。这些数据表明，k（off）率测量可以提高过继免疫治疗的可预测性，并提供关于T细胞体内质量的诊断信息。
Adoptive immunotherapy is a promising therapeutic approach for the treatment of chronic infections and cancer. T cells within a certain range of high avidity for their cognate ligand are believed to be most effective. T cell receptor (TCR) transfer experiments indicate that a major part of avidity is hardwired within the structure of the TCR. Unfortunately, rapid measurement of structural avidity of TCRs is difficult on living T cells. We developed a technology where dissociation (k(off) rate) of truly monomeric peptide-major histocompatibility complex (pMHC) molecules bound to surface-expressed TCRs can be monitored by real-time microscopy in a highly reliable manner. A first evaluation of this method on distinct human cytomegalovirus (CMV)-specific T cell populations revealed unexpected differences in the k(off) rates. CMV-specific T cells are currently being evaluated in clinical trials for efficacy in adoptive immunotherapy; therefore, determination of koff rates could guide selection of the most effective donor cells. Indeed, in two different murine infection models, we demonstrate that T cell populations with lower k(off) rates confer significantly better protection than populations with fast k(off) rates. These data indicate that k(off) rate measurements can improve the predictability of adoptive immunotherapy and provide diagnostic information on the in vivo quality of T cells.