Regeneron Pharmaceuticals, Inc., Tarrytown, NY, 10591, USA.
Nat Commun. 2023 Apr 26;14(1):2401. doi: 10.1038/s41467-023-37532-7.
The recognition of antigenic peptide-MHC (pMHC) molecules by T-cell receptors (TCR) initiates the T-cell mediated immune response. Structural characterization is key for understanding the specificity of TCR-pMHC interactions and informing the development of therapeutics. Despite the rapid rise of single particle cryoelectron microscopy (cryoEM), x-ray crystallography has remained the preferred method for structure determination of TCR-pMHC complexes. Here, we report cryoEM structures of two distinct full-length α/β TCR-CD3 complexes bound to their pMHC ligand, the cancer-testis antigen HLA-A2/MAGEA4 (230-239). We also determined cryoEM structures of pMHCs containing MAGEA4 (230-239) peptide and the closely related MAGEA8 (232-241) peptide in the absence of TCR, which provided a structural explanation for the MAGEA4 preference displayed by the TCRs. These findings provide insights into the TCR recognition of a clinically relevant cancer antigen and demonstrate the utility of cryoEM for high-resolution structural analysis of TCR-pMHC interactions.
T 细胞受体 (TCR) 识别抗原肽-MHC (pMHC) 分子，启动 T 细胞介导的免疫反应。结构特征对于理解 TCR-pMHC 相互作用的特异性以及指导治疗药物的开发至关重要。尽管单颗粒冷冻电子显微镜 (cryoEM) 的快速发展，但 X 射线晶体学仍然是 TCR-pMHC 复合物结构测定的首选方法。在这里，我们报告了两种不同全长 α/β TCR-CD3 复合物与它们的 pMHC 配体 HLA-A2/MAGEA4（230-239）结合的 cryoEM 结构。我们还确定了在没有 TCR 的情况下含有 MAGEA4（230-239）肽和密切相关的 MAGEA8（232-241）肽的 pMHC 的 cryoEM 结构，这为 TCR 显示的 MAGEA4 偏好提供了结构解释。这些发现为 TCR 对临床相关癌症抗原的识别提供了深入了解，并展示了 cryoEM 在 TCR-pMHC 相互作用的高分辨率结构分析中的应用。
