Molecular design of the γδT cell receptor ectodomain encodes biologically fit ligand recognition in the absence of mechanosensing.
Molecular design of the γδT cell receptor ectodomain encodes biologically fit ligand recognition in the absence of mechanosensing.
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DOI：
10.1073/pnas.2023050118
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发表时间：
2021-06-29
影响因子：
11.1
通讯作者：
Reinherz EL
中科院分区：
文献类型：
--
作者：
Mallis RJ;Duke-Cohan JS;Das DK;Akitsu A;Luoma AM;Banik D;Stephens HM;Tetteh PW;Castro CD;Krahnke S;Hussey RE;Lawney B;Brazin KN;Reche PA;Hwang W;Adams EJ;Lang MJ;Reinherz EL
TCR机械传感被认为是αβT细胞对稀少pMHC抗原反应的数字敏感性所必需的。我们使用生物信息学分析、分子动力学、单分子光钳技术、细胞激活和rna-seq分析来探索γδT细胞谱系中的这一范例。我们发现，与其在识别丰富的细胞表面配体方面的作用一致，γδTCR缺乏αβT细胞机械感觉的力依赖特征。与主要组织相容性复合体分子(PMHC)结合的多肽的高敏感度αβT细胞受体(TCR)识别需要机械传感，这一过程是微微牛顿(PN)生物作用力对αβTCR-pMHC键施加物理载荷以动态改变其寿命并促进数字敏感性细胞信号传递的过程。虽然机械转导对于αβT细胞系中的αβTCR和前TCR都是有效的，但它在γδT细胞中的作用尚不清楚。在这里，我们发现与CD1d结合的磺基糖脂硫脂的人DP10.7CDTCR只有在结合界面-远端γδ恒定结构域(C)模块被γδ的αβ模块取代时才能承受显著的负载并经历力诱导的结构转变。嵌合的γδ-αβTCR也比野生型(WT)γδTCR信号更强，这与结构、单分子和分子动力学研究一致，反映了−/−TCR是通过更规范的免疫球蛋白样受体相互作用介导识别的。缺乏与力相关的强健的捕获键，以及γδTcR结构转变，意味着γδT细胞不使用机械传感来识别配体。这种区别与这样一个事实是一致的，即它们的先天类型配体，包括细胞应激的标志，相对于排列在激活靶细胞上的稀疏的αβT细胞的pMHC配体，以高拷贝数表达。我们假设，机械感知出现在∼2亿年的脊椎动物进化过程中，以满足αβT细胞谱系中对pMHC的必不可少的适应性免疫识别要求，而非γδT细胞谱系的非pMHC配体检测机制是不必要的。
TCR mechanosensing is thought necessary for digital sensitivity of αβT cell response to scant pMHC antigens. We use bioinformatic analysis, molecular dynamics, single-molecule optical tweezers techniques, cellular activation, and RNA-seq analysis to explore this paradigm in the γδT cell lineage. We find that, in keeping with its role in recognizing abundant cell-surface ligands, the γδTCR lacks force-dependent hallmarks of mechanosensing in αβT cells. High-acuity αβT cell receptor (TCR) recognition of peptides bound to major histocompatibility complex molecules (pMHCs) requires mechanosensing, a process whereby piconewton (pN) bioforces exert physical load on αβTCR–pMHC bonds to dynamically alter their lifetimes and foster digital sensitivity cellular signaling. While mechanotransduction is operative for both αβTCRs and pre-TCRs within the αβT lineage, its role in γδT cells is unknown. Here, we show that the human DP10.7 γδTCR specific for the sulfoglycolipid sulfatide bound to CD1d only sustains a significant load and undergoes force-induced structural transitions when the binding interface-distal γδ constant domain (C) module is replaced with that of αβ. The chimeric γδ–αβTCR also signals more robustly than does the wild-type (WT) γδTCR, as revealed by RNA-sequencing (RNA-seq) analysis of TCR-transduced Rag2−/− thymocytes, consistent with structural, single-molecule, and molecular dynamics studies reflective of γδTCRs as mediating recognition via a more canonical immunoglobulin-like receptor interaction. Absence of robust, force-related catch bonds, as well as γδTCR structural transitions, implies that γδT cells do not use mechanosensing for ligand recognition. This distinction is consonant with the fact that their innate-type ligands, including markers of cellular stress, are expressed at a high copy number relative to the sparse pMHC ligands of αβT cells arrayed on activating target cells. We posit that mechanosensing emerged over ∼200 million years of vertebrate evolution to fulfill indispensable adaptive immune recognition requirements for pMHC in the αβT cell lineage that are unnecessary for the γδT cell lineage mechanism of non-pMHC ligand detection.
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影响因子：
7.3
作者：
Brazin KN;Mallis RJ;Das DK;Feng Y;Hwang W;Wang JH;Wagner G;Lang MJ;Reinherz EL
通讯作者：
Reinherz EL
影响因子：
56.9
作者：
Adams, EJ;Chien, YH;Garcia, KC
通讯作者：
Garcia, KC
影响因子：
29.7
作者：
Blum JS;Wearsch PA;Cresswell P
通讯作者：
Cresswell P
影响因子：
30.5
作者：
Adams, Erin J.;Strop, Pavel;Garcia, K. Christopher
通讯作者：
Garcia, K. Christopher
DOI：
10.1073/pnas.82.23.8158
发表时间：
1985-01-01
影响因子：
11.1
作者：
CANTRELL, DA;DAVIES, AA;CRUMPTON, MJ
通讯作者：
CRUMPTON, MJ