Evidence for a TCR Affinity Threshold Delimiting Maximal CD8 T Cell Function
Evidence for a TCR Affinity Threshold Delimiting Maximal CD8 T Cell Function
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DOI：
10.4049/jimmunol.1000173
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发表时间：
2010-05-01
影响因子：
4.4
通讯作者：
Rufer, Nathalie
中科院分区：
文献类型：
--
作者：
Schmid, Daphne A.;Irving, Melita B.;Rufer, Nathalie
保护性适应性免疫反应依赖于TCR介导的对自身MHC分子呈现的银衍生肽的识别。然而，自身Ag（肿瘤）特异性TCR通常具有太低的亲和力而不能实现最佳功能。为了精确评估TCR-肽-MHC结合参数与T细胞功能之间的关系，我们测试了一组序列优化的HLA-A*0201/NY-ESO-1（157-165）特异性TCR变体，其亲和力位于生理边界内以保持抗原特异性并避免交叉反应性，以及两个离群值（即，非常高和低亲和力的TCR）。用这些TCR转导的原代人CD 8 T细胞证明了TCR亲和力和亲合力的结合测量与T细胞的生物学应答（例如TCR细胞表面聚集、细胞内信号传导、增殖和靶细胞裂解）之间的稳健相关性。引人注目的是，在确定的TCR-肽-MHC亲和力阈值（K-D <类似于5 μ M）之上，T细胞功能不能进一步增强，揭示了最大T细胞功能的平台期，这与具有略微不同亲和力的多种TCR同等（共显性）参与免疫应答的概念相一致。我们提出，合理设计改进的自身特异性TCR可能不需要优化超过给定的亲和力阈值，以实现最佳的T细胞功能和避免交叉反应性的不可预测的风险。免疫学杂志，2010，184：4936-4946。
Protective adaptive immune responses rely on TCR-mediated recognition of Ag-derived peptides presented by self-MHC molecules. However, self-Ag (tumor)-specific TCRs are often of too low affinity to achieve best functionality. To precisely assess the relationship between TCR-peptide-MHC binding parameters and T cell function, we tested a panel of sequence-optimized HLA-A*0201/NY-ESO-1(157-165) specific TCR variants with affinities lying within physiological boundaries to preserve antigenic specificity and avoid cross-reactivity, as well as two outliers (i.e., a very high- and a low-affinity TCR). Primary human CD8 T cells transduced with these TCRs demonstrated robust correlations between binding measurements of TCR affinity and avidity and the biological response of the T cells, such as TCR cell-surface clustering, intracellular signaling, proliferation, and target cell lysis. Strikingly, above a defined TCR-peptide-MHC affinity threshold (K-D < similar to 5 mu M), T cell function could not be further enhanced, revealing a plateau of maximal T cell function, compatible with the notion that multiple TCRs with slightly different affinities participate equally (codominantly) in immune responses. We propose that rational design of improved self-specific TCRs may not need to be optimized beyond a given affinity threshold to achieve both optimal T cell function and avoidance of the unpredictable risk of cross-reactivity. The Journal of Immunology, 2010, 184: 4936-4946.