Álvaro-Benito Miguel, Freund Christian
Laboratory of Protein Biochemistry, Institute für Chemie und Biochemie, Department of Biology, Chemistry, Pharmacy, Freie Universität Berlin, Berlin, Germany.
HLA. 2020 Oct;96(4):415-429. doi: 10.1111/tan.14007. Epub 2020 Aug 27.
The nonclassical major histocompatibility complex of class II molecules (ncMHCII) HLA-DM (DM) and HLA-DO (DO) feature essential functions for the selection of the peptides that are displayed by classical MHCII proteins (MHCII) for CD4 T cell surveillance. Thus, although the binding groove of classical MHCII dictates the main features of the peptides displayed, ncMHCII function defines the preferential loading of peptides from specific cellular compartments and the extent to which they are presented. DM acts as a chaperone for classical MHCII molecules facilitating peptide exchange and thereby favoring the binding of peptide-MHCII complexes of high kinetic stability mostly in late endosomal compartments. DO on the other hand binds to DM blocking its peptide-editing function in B cells and thymic epithelial cells, limiting DM activity in these cellular subsets. DM and DO distinct expression patterns therefore define specific antigen presentation profiles that select unique peptide pools for each set of antigen presenting cell. We have come a long way understanding the mechanistic underpinnings of such distinct editing profiles and start to grasp the implications for ncMHCII biological function. DM acts as filter for the selection of immunodominant, pathogen-derived epitopes while DO blocks DM activity under certain physiological conditions to promote tolerance to self. Interestingly, recent findings have shown that the unexplored and neglected ncMHCII genetic diversity modulates retroviral infection in mouse, and affects human ncMHCII function. This review aims at highlighting the importance of ncMHCII function for CD4 T cell responses while integrating and evaluating what could be the impact of distinct editing profiles because of natural genetic variations.
非经典的II类主要组织相容性复合体（ncMHCII）中的HLA-DM（DM）和HLA-DO（DO）在选择由经典MHCII蛋白（MHCII）呈递给CD4 T细胞进行监测的肽段方面具有重要功能。因此，尽管经典MHCII的结合凹槽决定了所呈递肽段的主要特征，但ncMHCII的功能决定了来自特定细胞区室的肽段的优先装载及其呈递程度。DM作为经典MHCII分子的伴侣，促进肽段交换，从而有利于在晚期内体区室中形成高动力学稳定性的肽-MHCII复合物。另一方面，DO与DM结合，在B细胞和胸腺上皮细胞中阻断其肽段编辑功能，限制了这些细胞亚群中的DM活性。因此，DM和DO不同的表达模式定义了特定的抗原呈递谱，为每组抗原呈递细胞选择独特的肽库。我们在理解这种不同编辑谱的机制基础方面已经取得了很大进展，并开始理解其对ncMHCII生物学功能的影响。DM作为筛选免疫显性、病原体衍生表位的过滤器，而DO在某些生理条件下阻断DM活性以促进对自身的耐受性。有趣的是，最近的研究结果表明，未被探索和忽视的ncMHCII基因多样性可调节小鼠的逆转录病毒感染，并影响人类ncMHCII的功能。本综述旨在强调ncMHCII功能对CD4 T细胞反应的重要性，同时整合和评估由于自然遗传变异导致的不同编辑谱可能产生的影响。
