Mørch Alexander M, Bálint Štefan, Santos Ana Mafalda, Davis Simon J, Dustin Michael L
The Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom.
Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.
Front Cell Dev Biol. 2020 Oct 16;8:597627. doi: 10.3389/fcell.2020.597627. eCollection 2020.
The T-cell coreceptors CD4 and CD8 have well-characterized and essential roles in thymic development, but how they contribute to immune responses in the periphery is unclear. Coreceptors strengthen T-cell responses by many orders of magnitude - beyond a million-fold according to some estimates - but the mechanisms underlying these effects are still debated. T-cell receptor (TCR) triggering is initiated by the binding of the TCR to peptide-loaded major histocompatibility complex (pMHC) molecules on the surfaces of other cells. CD4 and CD8 are the only T-cell proteins that bind to the same pMHC ligand as the TCR, and can directly associate with the TCR-phosphorylating kinase Lck. At least three mechanisms have been proposed to explain how coreceptors so profoundly amplify TCR signaling: (1) the Lck recruitment model and (2) the pseudodimer model, both invoked to explain receptor triggering , and (3) two-step coreceptor recruitment to partially triggered TCRs leading to signal amplification. More recently it has been suggested that, in addition to initiating or augmenting TCR signaling, coreceptors effect antigen discrimination. But how can any of this be reconciled with TCR signaling occurring in the absence of CD4 or CD8, and with their interactions with pMHC being among the weakest specific protein-protein interactions ever described? Here, we review each theory of coreceptor function in light of the latest structural, biochemical, and functional data. We conclude that the oldest ideas are probably still the best, i.e., that their weak binding to MHC proteins and efficient association with Lck allow coreceptors to amplify weak incipient triggering of the TCR, without comprising TCR specificity.
T细胞共受体CD4和CD8在胸腺发育中具有明确且重要的作用，但它们如何在外周免疫反应中发挥作用尚不清楚。共受体可将T细胞反应增强多个数量级——据一些估计超过百万倍——但其作用机制仍存在争议。T细胞受体（TCR）的触发是由TCR与其他细胞表面负载肽的主要组织相容性复合体（pMHC）分子结合启动的。CD4和CD8是仅有的与TCR结合相同pMHC配体的T细胞蛋白，并且可以直接与TCR磷酸化激酶Lck结合。至少有三种机制被提出来解释共受体如何如此深刻地放大TCR信号：（1）Lck招募模型和（2）假二聚体模型，两者都被用来解释受体触发，以及（3）两步共受体招募到部分触发的TCR导致信号放大。最近有人提出，除了启动或增强TCR信号外，共受体还影响抗原识别。但这一切如何与在没有CD4或CD8的情况下发生的TCR信号以及它们与pMHC之间的相互作用（这是有史以来描述的最弱的特异性蛋白质-蛋白质相互作用之一）相协调呢？在这里，我们根据最新的结构、生化和功能数据回顾了共受体功能的每种理论。我们得出结论，最古老的观点可能仍然是最好的，即它们与MHC蛋白的弱结合以及与Lck的有效结合使共受体能够放大TCR的微弱初始触发，而不影响TCR的特异性。
