Structurally silent peptide anchor modifications allosterically modulate T cell recognition in a receptor-dependent manner.
Structurally silent peptide anchor modifications allosterically modulate T cell recognition in a receptor-dependent manner.
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结构沉默肽锚修饰以受体依赖性方式变构调节 T 细胞识别。
DOI：
10.1073/pnas.2018125118
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发表时间：
2021
影响因子：
11.1
通讯作者：
Baker,BrianM
中科院分区：
文献类型：
--
作者：
Smith,AngelaR;Alonso,JesusA;Ayres,CoryM;Singh,NishantK;Hellman,LanceM;Baker,BrianM
I类MHC蛋白呈递的多肽是T细胞对病原体和癌症免疫反应的基础。多肽结合亲和力和免疫原性之间的联系导致了具有更好的MHC结合的修饰多肽的设计，希望这些多肽能够有效地诱导针对其弱结合的、未修饰的对应物的交叉反应免疫反应。然而，越来越多的证据表明，T细胞受体(TCR)可以感知这种锚定修饰的多肽与野生型(WT)多肽不同，尽管区分的范围尚不清楚。我们在这里表明，即使在初级锚上没有明显的结构影响的修改也可以导致实质上更强或更弱的T细胞识别，这取决于TCR。令人惊讶的是，在远离修饰部位的区域，TCR可以感受到肽锚定修饰的效果，这表明了一种通过蛋白质的机制，即锚定残基作为TCR结合的变构调节剂。我们的发现强调在使用和解释锚定修饰多肽的结果时要谨慎，并对在其他情况下如何解释锚定修饰有意义，例如预测肿瘤新抗原的免疫原性。我们的数据也强调了更好地了解I类MHC蛋白的高度可调的动态性质以及这对各种形式的免疫识别的影响的重要需要。
Presentation of peptides by class I MHC proteins underlies T cell immune responses to pathogens and cancer. The association between peptide binding affinity and immunogenicity has led to the engineering of modified peptides with improved MHC binding, with the hope that these peptides would be useful for eliciting cross-reactive immune responses directed toward their weak binding, unmodified counterparts. Increasing evidence, however, indicates that T cell receptors (TCRs) can perceive such anchor-modified peptides differently than wild-type (WT) peptides, although the scope of discrimination is unclear. We show here that even modifications at primary anchors that have no discernible structural impact can lead to substantially stronger or weaker T cell recognition depending on the TCR. Surprisingly, the effect of peptide anchor modification can be sensed by a TCR at regions distant from the site of modification, indicating a through-protein mechanism in which the anchor residue serves as an allosteric modulator for TCR binding. Our findings emphasize caution in the use and interpretation of results from anchor-modified peptides and have implications for how anchor modifications are accounted for in other circumstances, such as predicting the immunogenicity of tumor neoantigens. Our data also highlight an important need to better understand the highly tunable dynamic nature of class I MHC proteins and the impact this has on various forms of immune recognition.