HLA-DM allotypes - Distinct editing functions of natural HLA-DM allotypes impact antigen presentation and CD4+ T cell activation

Major Histocompatibility Complex of Class II (MHCII) antigen presentation is a key event of adaptive immunity. HLA-DM favors the presentation of kinetically stable peptide-MHCII complexes but does not bind peptides itself and exhibits only a low degree of polymorphism. To date, no evidence for altered function of DM due to natural variations has been reported. We define the presence of DM haplotypes in human populations covered by the 1000 Genomes Project and probe their activity in antigen presentation assays. Our results indicate a clear linkage between DMA*0103 and DMB*0107 never reported before. Thehe corresponding heterodimer features a distinct activity profile when compared to the most frequent allotype (DMA*0101-DMB*0101). In vitro experiments demonstrate a broader pH activity profile for the new allotype, explaining its characteristic cellular function. Together, our results suggest that natural variations of DM have important consequences for an individual’s adaptive immune response.

主要组织相容性复合体II类（Major Histocompatibility Complex of Class II, MHCII）抗原提呈是适应性免疫的关键事件。人类白细胞抗原DM（HLA-DM）可促进动力学稳定的肽-MHCII复合物（peptide-MHCII complexes）的提呈，但自身并不结合肽段，且仅具有较低的多态性。迄今为止，尚无关于自然变异导致DM功能改变的相关报道。我们明确了千人基因组计划（1000 Genomes Project）所覆盖的人类群体中DM单倍型（haplotype）的存在情况，并在抗原提呈实验中检测了它们的活性。本研究结果显示，DMA*0103与DMB*0107之间存在此前从未被报道过的显著连锁关系。与之对应的异二聚体（heterodimer）与最常见的同种异型（allotype）DMA*0101-DMB*0101相比，具有独特的活性谱。体外实验表明，该新型同种异型具有更宽泛的pH活性谱，这解释了其特有的细胞功能。综上，我们的研究结果提示，DM的自然变异对个体的适应性免疫应答具有重要影响。