CD8 coreceptor-mediated focusing can reorder the agonist hierarchy of peptide ligands recognized via the T cell receptor.
CD8 coreceptor-mediated focusing can reorder the agonist hierarchy of peptide ligands recognized via the T cell receptor.
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DOI：
10.1073/pnas.2019639118
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发表时间：
2021-07-20
影响因子：
11.1
通讯作者：
Wooldridge L
中科院分区：
文献类型：
--
作者：
Clement M;Knezevic L;Dockree T;McLaren JE;Ladell K;Miners KL;Llewellyn-Lacey S;Rubina A;Francis O;Cole DK;Sewell AK;Bridgeman JS;Price DA;van den Berg HA;Wooldridge L
有限宿主内肽宇宙的足够免疫覆盖需要高度简并的T细胞受体（TCR）。然而，这种对抗原交叉识别的内在需求与自身免疫的高风险相关，这只能通过适应性特异性的过程来减轻。我们描述了一种机制，解决了这个难题，允许个人的克隆型集中在特定的肽配体，而不改变的TCR的结构。CD 8 + T细胞具有固有的交叉反应性，并通过克隆型表达的T细胞受体（TCR）在给定的主要组织相容性复合体I类（MHCI）分子的背景下识别许多肽抗原。线性表达的辅助受体CD 8与MHCI在一个独特且基本不变的位点协同相互作用，以减缓TCR/肽-MHCI（pMHCI）解离速率并增强抗原敏感性。然而，这种生物学效应不一定是一致的，理论模型表明，抗原敏感性可以通过CD 8以不同的方式调节。我们使用两个内在控制系统来确定TCR/pMHCI相互作用和pMHCI/CD 8相互作用之间的关系如何影响抗原识别的功能灵敏度。我们的数据表明，pMHCI/CD 8相互作用的调节可以在TCR的亲和力谱上重新排列肽配体的激动剂层次。
Sufficient immune coverage of the peptide universe within a finite host requires highly degenerate T cell receptors (TCRs). However, this inherent need for antigen cross-recognition is associated with a high risk of autoimmunity, which can only be mitigated by a process of adaptable specificity. We describe a mechanism that resolves this conundrum by allowing individual clonotypes to focus on specific peptide ligands without alterations to the structure of the TCR. CD8+ T cells are inherently cross-reactive and recognize numerous peptide antigens in the context of a given major histocompatibility complex class I (MHCI) molecule via the clonotypically expressed T cell receptor (TCR). The lineally expressed coreceptor CD8 interacts coordinately with MHCI at a distinct and largely invariant site to slow the TCR/peptide-MHCI (pMHCI) dissociation rate and enhance antigen sensitivity. However, this biological effect is not necessarily uniform, and theoretical models suggest that antigen sensitivity can be modulated in a differential manner by CD8. We used two intrinsically controlled systems to determine how the relationship between the TCR/pMHCI interaction and the pMHCI/CD8 interaction affects the functional sensitivity of antigen recognition. Our data show that modulation of the pMHCI/CD8 interaction can reorder the agonist hierarchy of peptide ligands across a spectrum of affinities for the TCR.
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DOI：
10.1084/jem.20030170
发表时间：
2003-06-16
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Bosselut R;Guinter TI;Sharrow SO;Singer A
通讯作者：
Singer A
影响因子：
64.5
作者：
Moody, AM;Chui, D;Reinherz, EL
通讯作者：
Reinherz, EL
影响因子：
64.8
作者：
Gao, GF;Tormo, J;Jakobsen, BK
通讯作者：
Jakobsen, BK
影响因子：
4.4
作者：
Sommermeyer, Daniel;Uckert, Wolfgang
通讯作者：
Uckert, Wolfgang
影响因子：
4.8
作者：
Purbhoo, MA;Boulter, JM;Sewell, AK
通讯作者：
Sewell, AK