How nonuniform contact profiles of T cell receptors modulate thymic selection outcomes
How nonuniform contact profiles of T cell receptors modulate thymic selection outcomes
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T 细胞受体的不均匀接触特征如何调节胸腺选择结果
DOI：
10.1103/physreve.97.032413
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发表时间：
2018
影响因子：
2.4
通讯作者：
Kardar, Mehran
中科院分区：
文献类型：
--
作者：
Chen, Hanrong;Chakraborty, Arup K.;Kardar, Mehran
T 细胞受体 (TCR) 结合附着在主要组织相容性复合体 (MHC) 分子上的外源肽或自身肽，这种相互作用的强度决定了 T 细胞的激活。优化 T 细胞识别多种外源肽并耐受自身肽的能力对于适应性免疫系统正常发挥作用至关重要。这是通过选择胸腺中的 T 细胞来实现的，其中表达独特、随机生成的 TCR 的未成熟 T 细胞与大量自肽-MHC 相互作用；如果TCR与任何自肽-MHC的结合不够强，或者与至少一种自肽-MHC的结合太强，T细胞就会死亡。过去的理论工作将胸腺选择视为一个极值问题，并描述了选择后 TCR 库中氨基酸的统计富集或消耗，表明 T 细胞如何被选择为能够特异性识别来自不同病原体的肽，但自身反应性有限。在这里，我们研究了当 TCR 与肽-MHC 不均匀接触时，选择后 TCR 库的多样性如何被改变。具体来说，我们的动机是最近的实验表明 TCR 序列某些位置的氨基酸对胸腺选择结果有很大影响，并且晶体结构数据揭示了 TCR 与其肽-MHC 配体之间的不均匀接触特征。使用代表性的 TCR 接触曲线作为说明，我们通过模拟表明氨基酸的统计富集或消耗现在根据接触曲线随位置而变化，而且重要的是，它取决于胸腺选择过程中非均匀接触的实施。我们通过分析来解释这些重要的结果。我们的研究对于理解影响选择后 TCR 功能的选择力量具有重要意义。
T cell receptors (TCRs) bind foreign or self-peptides attached to major histocompatibility complex (MHC) molecules, and the strength of this interaction determines T cell activation. Optimizing the ability of T cells to recognize a diversity of foreign peptides yet be tolerant of self-peptides is crucial for the adaptive immune system to properly function. This is achieved by selection of T cells in the thymus, where immature T cells expressing unique, stochastically generated TCRs interact with a large number of self-peptide-MHC; if a TCR does not bind strongly enough to any self-peptide-MHC, or too strongly with at least one self-peptide-MHC, the T cell dies. Past theoretical work cast thymic selection as an extreme value problem and characterized the statistical enrichment or depletion of amino acids in the postselection TCR repertoire, showing how T cells are selected to be able to specifically recognize peptides derived from diverse pathogens yet have limited self-reactivity. Here, we investigate how the diversity of the postselection TCR repertoire is modified when TCRs make nonuniform contacts with peptide-MHC. Specifically, we were motivated by recent experiments showing that amino acids at certain positions of a TCR sequence have large effects on thymic selection outcomes, and crystal structure data that reveal a nonuniform contact profile between a TCR and its peptide-MHC ligand. Using a representative TCR contact profile as an illustration, we show via simulations that the statistical enrichment or depletion of amino acids now varies by position according to the contact profile, and, importantly, it depends on the implementation of nonuniform contacts during thymic selection. We explain these nontrivial results analytically. Our study has implications for understanding the selection forces that shape the functionality of the postselection TCR repertoire.