Presentation of antigenic peptides by major histocompatibility complex class II (MHC-II) proteins determines T helper cell reactivity. The MHC-II genetic locus displays a large degree of allelic polymorphism influencing the peptide repertoire presented by the resulting MHC-II protein allotypes. During antigen processing, the human leukocyte antigen (HLA) molecule HLA-DM (DM) encounters these distinct allotypes and catalyzes exchange of the placeholder peptide CLIP by exploiting dynamic features of MHC-II. Here, we investigate 12 highly abundant CLIP-bound HLA-DRB1 allotypes and correlate dynamics to catalysis by DM. Despite large differences in thermodynamic stability, peptide exchange rates fall into a target range that maintains DM responsiveness. A DM-susceptible conformation is conserved in MHC-II molecules, and allosteric coupling between polymorphic sites affects dynamic states that influence DM catalysis. As exemplified for rheumatoid arthritis, we postulate that intrinsic dynamic features of peptide–MHC-II complexes contribute to the association of individual MHC-II allotypes with autoimmune disease.

主要组织相容性复合物 II 类 (MHC-II) 蛋白呈递的抗原肽决定了 T 辅助细胞的反应性。MHC-II 遗传位点表现出很大程度的等位基因多态性，影响由所得 MHC-II 蛋白同种异型呈现的肽库。在抗原加工过程中，人类白细胞抗原 (HLA) 分子 HLA-DM (DM) 遇到这些不同的同种异型，并通过利用 MHC-II 的动态特征催化占位肽 CLIP 的交换。在这里，我们研究了 12 种高丰度的 CLIP 结合 HLA-DRB1 同种异型，并将动力学与 DM 的催化相关联。尽管热力学稳定性存在很大差异，但肽交换率仍处于维持 DM 反应性的目标范围内。DM 敏感构象在 MHC-II 分子中是保守的，多态位点之间的变构耦合会影响影响 DM 催化的动态状态。以类风湿性关节炎为例，我们假设肽-MHC-II 复合物的内在动态特征有助于个体 MHC-II 同种异型与自身免疫性疾病的关联。