Xenolaüs Genetics LLC, Los Angeles, CA, United States.
Mol Immunol. 2022 Apr;144:138-151. doi: 10.1016/j.molimm.2021.11.015. Epub 2022 Feb 24.
The mechanism which adapts the T-cell antigen receptor (TCR) within a given major histocompatibility complex (MHC/HLA) genotype is essential for protection against pathogens. Historically attributed to relative affinity, genetically vast TCRs are surprisingly focused towards a micromolar affinity for their respective peptide (p) plus MHC (pMHC) ligands. Thus, the somatic diversity of the TCR with respect to MHC-restriction, and (ultimately) to pathogens, remains enigmatic. Here, we derive a triple integral solution (from fixed geometry) for any given V domain in TCR bound to pMHC. Solved complexes involving HLA-DR and HLA-DQ, where genetic linkage to the TCR is most profound, were examined in detail. Certain V domains displayed rare geometry within this panel-specifying a restricted rotational probability/volumetric density (dV). Remarkably, hydrogen (H) bond charge-relays distinguished these structures from the others; suggesting that CDR3 binding chemistry dictates CDR2 contacts on the opposite MHC-II alpha helix. Together, these data suggest that TCR recapitulate dV and specialise target pMHC recognition. As such, there are implications for the design of TCR-based therapeutics.
在特定的主要组织相容性复合体 (MHC/HLA) 基因型内适应 T 细胞抗原受体 (TCR) 的机制对于抵御病原体至关重要。该机制传统上归因于相对亲和力，但实际上，TCR 具有广泛的遗传多样性，其对各自的肽 (p) 加 MHC (pMHC) 配体的亲和力却惊人地集中在微摩尔范围内。因此，TCR 相对于 MHC 限制（最终是针对病原体）的体细胞多样性仍然是一个谜。在这里，我们从固定的几何形状出发，为 TCR 与 pMHC 结合的任何给定 V 结构域推导出三重积分解。我们详细检查了与 TCR 遗传联系最紧密的 HLA-DR 和 HLA-DQ 结合的复合物。在这个面板中，某些 V 结构域显示出罕见的几何形状，指定了受限的旋转概率/体积密度 (dV)。值得注意的是，氢键电荷传递将这些结构与其他结构区分开来；这表明 CDR3 结合化学决定了相反 MHC-II α 螺旋上的 CDR2 接触。这些数据表明 TCR 可以重现 dV 并专门识别目标 pMHC。因此，这对基于 TCR 的治疗药物的设计具有重要意义。
