Ng Chau Kevin, George Jason T, Onuchic José N, Lin Xingcheng, Levine Herbert
Physics Department, Northeastern University, Boston, Massachusetts 02115, USA.
Center for Theoretical Biological Physics, Rice University, Houston, Texas 77005, USA.
Phys Rev E. 2022 Jul;106(1-1):014406. doi: 10.1103/PhysRevE.106.014406.
The T-cell arm of the adaptive immune system provides the host protection against unknown pathogens by discriminating between host and foreign material. This discriminatory capability is achieved by the creation of a repertoire of cells each carrying a T-cell receptor (TCR) specific to non-self-antigens displayed as peptides bound to the major histocompatibility complex (pMHC). The understanding of the dynamics of the adaptive immune system at a repertoire level is complex, due to both the nuanced interaction of a TCR-pMHC pair and to the number of different possible TCR-pMHC pairings, making computationally exact solutions currently unfeasible. To gain some insight into this problem, we study an affinity-based model for TCR-pMHC binding in which a crystal structure is used to generate a distance-based contact map that weights the pairwise amino acid interactions. We find that the TCR-pMHC binding energy distribution strongly depends both on the number of contacts and the repeat structure allowed by the topology of the contact map of choice; this in turn influences T-cell recognition probability during negative selection, with higher variances leading to higher survival probabilities. In addition, we quantify the degree to which neoantigens with mutations in sites with higher contacts are recognized at a higher rate.
适应性免疫系统的T细胞分支通过区分自身和外来物质为宿主提供针对未知病原体的保护。这种区分能力是通过创建一组细胞来实现的，每个细胞都携带一种T细胞受体（TCR），该受体特异性识别以与主要组织相容性复合体结合的肽形式展示的非自身抗原（pMHC）。由于TCR-pMHC对之间的细微相互作用以及不同可能的TCR-pMHC配对数量，在库水平上理解适应性免疫系统的动力学很复杂，这使得目前计算精确解不可行。为了深入了解这个问题，我们研究了一种基于亲和力的TCR-pMHC结合模型，其中利用晶体结构生成基于距离的接触图，该图对成对氨基酸相互作用进行加权。我们发现，TCR-pMHC结合能分布强烈依赖于接触数量以及所选接触图拓扑结构允许的重复结构；这反过来又影响阴性选择期间的T细胞识别概率，方差越高，存活概率越高。此外，我们量化了在接触较多位点发生突变的新抗原被更高频率识别的程度。
