Coreceptor affinity for MHC defines peptide specificity requirements for TCR interaction with coagonist peptide-MHC.
Coreceptor affinity for MHC defines peptide specificity requirements for TCR interaction with coagonist peptide-MHC.
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DOI：
10.1084/jem.20122528
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发表时间：
2013-08-26
期刊：
影响因子：
--
通讯作者：
Gascoigne NR
中科院分区：
文献类型：
--
作者：
Hoerter JA;Brzostek J;Artyomov MN;Abel SM;Casas J;Rybakin V;Ampudia J;Lotz C;Connolly JM;Chakraborty AK;Gould KG;Gascoigne NR
TCR与辅激剂相互作用的需求随着CD8-I类相互作用强度的增加而减少。共激剂是内源性MHC-肽复合体，本身不激活T细胞。最近的研究表明，非刺激性内源性多肽可以增强T细胞对抗原的识别，但MHCI和MHCII限制性系统产生的结果截然不同。MHCII限制的TCR需要与非刺激性多肽-MHC(PMHC)相互作用，显示出对激活增强剂或辅激剂的多肽特异性。相反，到目前为止所研究的MHCI限制性细胞没有显示出对共激剂的这种肽特异性，这表明CD8与非同源MHCI结合更重要。在这里，我们展示了如何通过改变CD8和TCR与激动剂和辅助剂的结合结合计算机模拟来解决这种二分性，并识别了CD8影响共激剂的多肽特异性的两种不同的机制。机制1确定了CD8与非同源配体结合的要求，并表明共激动剂pMHCI的CD8亲和力与共激动剂CD8的亲和力之间存在直接关系。机制2描述了CD8与激动剂pMHCI的亲和力如何改变了对特定辅激动剂多肽的需求。CD8结合力强的MHC可以耐受所有或大部分多肽作为共激动剂，但CD8结合较弱的MHC需要更强的TCR与共激剂的结合，从而限制了潜在的共激性肽。在MHCI系统中的这些发现也解释了MHCII限制细胞中的肽特异性共生作用，因为CD4-MHCII相互作用通常比CD8-MHCI弱。
The requirement for the TCR to interact with coagonists, endogenous MHC–peptide complexes which do not themselves activate the T cell, decreases as the strength of the CD8–class I interaction increases. Recent work has demonstrated that nonstimulatory endogenous peptides can enhance T cell recognition of antigen, but MHCI- and MHCII-restricted systems have generated very different results. MHCII-restricted TCRs need to interact with the nonstimulatory peptide–MHC (pMHC), showing peptide specificity for activation enhancers or coagonists. In contrast, the MHCI-restricted cells studied to date show no such peptide specificity for coagonists, suggesting that CD8 binding to noncognate MHCI is more important. Here we show how this dichotomy can be resolved by varying CD8 and TCR binding to agonist and coagonists coupled with computer simulations, and we identify two distinct mechanisms by which CD8 influences the peptide specificity of coagonism. Mechanism 1 identifies the requirement of CD8 binding to noncognate ligand and suggests a direct relationship between the magnitude of coagonism and CD8 affinity for coagonist pMHCI. Mechanism 2 describes how the affinity of CD8 for agonist pMHCI changes the requirement for specific coagonist peptides. MHCs that bind CD8 strongly were tolerant of all or most peptides as coagonists, but weaker CD8-binding MHCs required stronger TCR binding to coagonist, limiting the potential coagonist peptides. These findings in MHCI systems also explain peptide-specific coagonism in MHCII-restricted cells, as CD4–MHCII interaction is generally weaker than CD8–MHCI.
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影响因子：
32.4
作者：
Liu, YW;Xiong, Y;Wang, JH
通讯作者：
Wang, JH
影响因子：
64.8
作者：
Alam, SM;Travers, PJ;Gascoigne, NRJ
通讯作者：
Gascoigne, NRJ
影响因子：
30.5
作者：
通讯作者：
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影响因子：
30.5
作者：
通讯作者：
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影响因子：
4.4
作者：
Devine, L;Rogozinski, L;Kavathas, PB
通讯作者：
Kavathas, PB