T cells can help confer protective immunity by eliminating infections and tumors or drive immunopathology by damaging host cells. Both outcomes require a series of steps from the activation of naïve T cells to their clonal expansion, differentiation and migration to tissue sites. In addition to specific recognition of the antigen via the T cell receptor (TCR), multiple accessory signals from costimulatory molecules, cytokines and metabolites also influence each step along the progression of the T cell response. Current efforts to modify effector T cell function in many clinical contexts focus on the latter - which encompass antigen-independent and broad, contextual regulators. Not surprisingly, such approaches are often accompanied by adverse events, as they also affect T cells not relevant to the specific treatment. In contrast, fine tuning T cell responses by precisely targeting antigen-specific TCR signals has the potential to radically alter therapeutic strategies in a focused manner. Development of such approaches, however, requires a better understanding of functioning of the TCR and the biochemical signaling network coupled to it. In this article, we review some of the recent advances which highlight important roles of TCR signals throughout the activation and differentiation of T cells during an immune response. We discuss how, an appreciation of specific signaling modalities and variant ligands that influence the function of the TCR has the potential to influence design principles for the next generation of pharmacologic and cellular therapies, especially in the context of tumor immunotherapies involving adoptive cell transfers.

中文翻译：

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为细胞免疫疗法操纵 TCR 信号网络：挑战与机遇。

T细胞可以通过消除感染和肿瘤来帮助赋予保护性免疫，或者通过破坏宿主细胞来驱动免疫病理学。这两种结果都需要从幼稚 T 细胞的激活到其克隆扩增、分化和迁移到组织部位的一系列步骤。除了通过 T 细胞受体 (TCR) 特异性识别抗原外，来自共刺激分子、细胞因子和代谢物的多种辅助信号也会影响 T 细胞反应进程中的每个步骤。目前在许多临床环境中改变效应 T 细胞功能的努力集中在后者——包括抗原独立和广泛的环境调节因子。毫不奇怪，这种方法通常伴随着不良事件，因为它们也会影响与特定治疗无关的 T 细胞。相比之下，通过精确靶向抗原特异性 TCR 信号来微调 T 细胞反应有可能以集中的方式从根本上改变治疗策略。然而，开发此类方法需要更好地了解 TCR 的功能以及与之耦合的生化信号网络。在本文中，我们回顾了一些最近的进展，这些进展突出了 TCR 信号在免疫反应过程中 T 细胞激活和分化过程中的重要作用。我们讨论了对影响 TCR 功能的特定信号传导方式和变异配体的认识如何有可能影响下一代药物和细胞疗法的设计原则，特别是在涉及过继细胞转移的肿瘤免疫疗法的背景下。