Class II human leucocyte antigen (HLA) proteins are involved in the immune response by presenting pathogen‐derived peptides to CD4⁺ T lymphocytes. At the molecular level, they are constituted by α/β‐heterodimers on the surface of professional antigen‐presenting cells. Here, we report that the acceptor variant (rs8084) in the HLA‐DRA gene mediates the transcription of an alternative version of the α‐chain lacking 25 amino acids in its extracellular domain. Molecular dynamics simulations suggest this isoform undergoes structural refolding which in turn affects its stability and cellular trafficking. The short HLA‐DRA isoform cannot reach the cell surface, although it is still able to bind the corresponding β‐chain. Conversely, it remains entrapped within the endoplasmic reticulum where it is targeted for degradation. Furthermore, we demonstrate that the short isoform can be transported to the cell membrane via interactions with the peptide‐binding site of canonical HLA heterodimers. Altogether, our findings indicate that short HLA‐DRA functions as a novel intact antigen for class II HLA molecules.

中文翻译：

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HLA-DRA 中的剪接受体变异影响 II 类 DR α 链的构象和细胞定位

^{II 类人类白细胞抗原 (HLA) 蛋白通过将病原体衍生肽呈递给 CD4 +} T 淋巴细胞而参与免疫反应。在分子水平上，它们由专业抗原呈递细胞表面的α/β-异二聚体构成。在这里，我们报告HLA ‐ DRA中的受体变体 (rs8084)基因介导在其细胞外结构域中缺乏 25 个氨基酸的 α 链的替代版本的转录。分子动力学模拟表明这种亚型经历了结构重折叠，进而影响其稳定性和细胞运输。短的 HLA-DRA 异构体不能到达细胞表面，尽管它仍然能够结合相应的 β 链。相反，它仍然被困在内质网中，在那里它成为降解的目标。此外，我们证明了短亚型可以通过与典型 HLA 异二聚体的肽结合位点相互作用而转运到细胞膜。总之，我们的研究结果表明，短 HLA-DRA 可作为 II 类 HLA 分子的新型完整抗原。