HLA-DMA Polymorphisms Differentially Affect MHC Class II Peptide Loading
HLA-DMA Polymorphisms Differentially Affect MHC Class II Peptide Loading
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DOI：
10.4049/jimmunol.1401389
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发表时间：
2015-01-15
影响因子：
4.4
通讯作者：
Freund, Christian
中科院分区：
文献类型：
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作者：
Alvaro-Benito, Miguel;Wieczorek, Marek;Freund, Christian
在适应性免疫应答过程中，MHCII蛋白在apc细胞表面显示抗原肽，用于CD4(+) T细胞的监视。HLA-DM是一种非经典MHCII蛋白，作为MHCII的肽交换催化剂，编辑肽库。虽然它们指向相同的基因位点，但MHCII蛋白表现出高度的多态性，而HLA-DM仅观察到低变异性。由于HLA-DM活性直接促进免疫优势肽的呈现，HLA-DM （DMA或DMB链）的多态性很可能是自身免疫和免疫疾病的一个危险因素。我们系统比较了DMA*0103/DMB*0101 （DMA- g155a和DMA- r184h）与DMA*0101/DMB*0101在催化肽交换和解离以及与几种HLA-DR/肽复合物的直接相互作用方面的作用，发现DMA*0103/DMB*0101的催化活性较弱。G155A取代通过降低肽释放速度而主导DMA*0103/DMB* 0101的催化行为。与DMA*0101/DMB*0101相比，预载肽- mhcii复合物在DMA*0103/DMB* 0101存在下的半衰期增加了2倍。我们发现，在高亲和力竞争肽存在的情况下，这种效应导致自身免疫相关Ags的更大持久性。因此，我们的研究表明，HLA-DM多态性残基对HLA-DM的催化活性有相当大的影响。
During the adaptive immune response, MHCII proteins display antigenic peptides on the cell surface of APCs for CD4(+) T cell surveillance. HLA-DM, a nonclassical MHCII protein, acts as a peptide exchange catalyst for MHCII, editing the peptide repertoire. Although they map to the same gene locus, MHCII proteins exhibit a high degree of polymorphism, whereas only low variability has been observed for HLA-DM. As HLA-DM activity directly favors immunodominant peptide presentation, polymorphisms in HLA-DM (DMA or DMB chain) might well be a contributing risk factor for autoimmunity and immune disorders. Our systematic comparison of DMA*0103/DMB*0101 (DMA-G155A and DMA-R184H) with DMA*0101/DMB*0101 in terms of catalyzed peptide exchange and dissociation, as well as direct interaction with several HLA-DR/peptide complexes, reveals an attenuated catalytic activity of DMA*0103/DMB*0101. The G155A substitution dominates the catalytic behavior of DMA*0103/DMB* 0101 by decreasing peptide release velocity. Preloaded peptide-MHCII complexes exhibit similar to 2-fold increase in half-life in the presence of DMA*0103/DMB* 0101 when compared with DMA*0101/DMB*0101. We show that this effect leads to a greater persistence of autoimmunity-related Ags in the presence of high-affinity competitor peptide. Our study therefore reveals that HLA-DM polymorphic residues have a considerable impact on HLA-DM catalytic activity.