Division of Rheumatology, Rosalind Russell and Ephraim P. Engleman Arthritis Research Center, Department of Medicine, University of California, San Francisco, San Francisco, CA, United States.
Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA, United States.
Front Immunol. 2021 Apr 16;12:673196. doi: 10.3389/fimmu.2021.673196. eCollection 2021.
Self- and non-self ligand discrimination is a core principle underlying T cell-mediated immunity. Mature αβ T cells can respond to a foreign peptide ligand presented by major histocompatibility complex molecules (pMHCs) on antigen presenting cells, on a background of continuously sensed self-pMHCs. How αβ T cells can properly balance high sensitivity and high specificity to foreign pMHCs, while surrounded by a sea of self-peptide ligands is not well understood. Such discrimination cannot be explained solely by the affinity parameters of T cell antigen receptor (TCR) and pMHC interaction. In this review, we will discuss how T cell ligand discrimination may be molecularly defined by events downstream of the TCR-pMHC interaction. We will discuss new evidence in support of the kinetic proofreading model of TCR ligand discrimination, and in particular how the kinetics of specific phosphorylation sites within the adaptor protein linker for activation of T cells (LAT) determine the outcome of TCR signaling. In addition, we will discuss emerging data regarding how some kinases, including ZAP-70 and LCK, may possess scaffolding functions to more efficiently direct their kinase activities.
自身和非自身配体的区分是 T 细胞介导免疫的核心原则。成熟的 αβ T 细胞可以对外来的肽配体做出反应，这些配体由主要组织相容性复合物分子（pMHCs）呈现在抗原呈递细胞上，同时还要不断感知自身的 pMHCs。然而，人们对于 αβ T 细胞如何在自身肽配体的海洋中正确地平衡对外来 pMHCs 的高敏感性和高特异性还知之甚少。这种区分不能仅仅用 T 细胞抗原受体（TCR）和 pMHC 相互作用的亲和力参数来解释。在这篇综述中，我们将讨论 T 细胞配体的区分如何可能通过 TCR-pMHC 相互作用下游的事件在分子水平上定义。我们将讨论支持 TCR 配体区分的动力学校验模型的新证据，特别是衔接蛋白激活 T 细胞的链接（LAT）中的特定磷酸化位点的动力学如何决定 TCR 信号转导的结果。此外，我们还将讨论一些激酶（包括 ZAP-70 和 LCK）如何可能具有支架功能，以更有效地指导其激酶活性的新出现的数据。
