T cell receptors (TCRs) orchestrate cellular immunity by recognizing peptides presented by a range of major histocompatibility complex (MHC) proteins. Naturally occurring TCRs bind the composite peptide/MHC surface, recognizing peptides that are structurally and chemically compatible with the TCR binding site. Here we describe a molecularly evolved TCR variant that binds the human class I MHC protein HLA-A2 independent of the bound peptide, achieved by a drastic perturbation of the TCR binding geometry that places the molecule far from the peptide binding groove. This unique geometry is unsupportive of normal T cell signaling. A substantial divergence between affinity measurements in solution and in two dimensions between proximal cell membranes leads us to attribute the lack of signaling to steric hindrance that limits binding in the confines of a cell–cell interface. Our results provide an example of how receptor binding geometry can impact T cell function and provide further support for the view that germline-encoded residues in TCR binding loops evolved to drive productive TCR recognition and signaling.

中文翻译：

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一种工程化的 T 细胞受体变体实现了功能结合模式的局限性

T 细胞受体 (TCR) 通过识别由一系列主要组织相容性复合体 (MHC) 蛋白呈递的肽来协调细胞免疫。天然存在的 TCR 结合复合肽/MHC 表面，识别在结构和化学上与 TCR 结合位点相容的肽。在这里，我们描述了一种分子进化的 TCR 变体，该变体结合人类 I 类 MHC 蛋白 HLA-A2，独立于结合的肽，通过 TCR 结合几何的剧烈扰动实现，使分子远离肽结合槽。这种独特的几何形状不支持正常的 T 细胞信号传导。溶液中亲和力测量和近端细胞膜之间的二维亲和力测量之间的显着差异导致我们将缺乏信号归因于空间位阻，限制了细胞 - 细胞界面范围内的结合。我们的结果提供了一个示例，说明受体结合几何结构如何影响 T 细胞功能，并为 TCR 结合环中的种系编码残基进化以驱动有效的 TCR 识别和信号传导的观点提供进一步支持。