Distinct editing functions of natural HLA-DM allotypes impact antigen presentation and CD4+ T cell activation
Distinct editing functions of natural HLA-DM allotypes impact antigen presentation and CD4+ T cell activation
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DOI：
10.1038/s41423-018-0181-1
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发表时间：
2020-02-01
影响因子：
24.1
通讯作者：
Freund, Christian
中科院分区：
文献类型：
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作者：
Alvaro-Benito, Miguel;Morrison, Eliot;Freund, Christian
主要组织相容性II类（MHCII）复合物的经典人类白细胞抗原（HLA）分子呈递用于CD 4（+）T细胞的发育、监视和活化的肽。非经典MHCII样蛋白HLA-DM（DM）催化肽交换和装载到MHCII分子上，从而形成MHCII免疫肽段。DM在蛋白质的两条链（DMA和DMB）中的自然变异已被假设影响肽呈递，但没有证据表明功能改变。在这里，我们定义了DM同种异型在1000个基因组计划所涵盖的人群中的存在，并探讨其活动。研究了几种同种异型的功能特性，并显示出DMA和DMB的特定组合对肽诱导的T细胞活化的强烈增强。生化证据表明，一个更广泛的pH活性曲线的新的变异相对于最常见的表达DM同种异型。免疫肽组分析表明，新的DM异源二聚体的隔室活性延伸到晚期内体之外，并表明当抗原绕过经典加工途径时，DM的自然变异对获得性免疫具有深远的影响。
Classical human leukocyte antigen (HLA) molecules of the major histocompatibility class II (MHCII) complex present peptides for the development, surveillance and activation of CD4(+) T cells. The nonclassical MHCII-like protein HLA-DM (DM) catalyzes the exchange and loading of peptides onto MHCII molecules, thereby shaping MHCII immunopeptidomes. Natural variations of DM in both chains of the protein (DMA and DMB) have been hypothesized to impact peptide presentation, but no evidence for altered function has been reported. Here we define the presence of DM allotypes in human populations covered by the 1000 Genomes Project and probe their activity. The functional properties of several allotypes are investigated and show strong enhancement of peptide-induced T cell activation for a particular combination of DMA and DMB. Biochemical evidence suggests a broader pH activity profile for the new variant relative to that of the most commonly expressed DM allotype. Immunopeptidome analysis indicates that the compartmental activity of the new DM heterodimer extends beyond the late endosome and suggests that the natural variation of DM has profound effects on adaptive immunity when antigens bypass the canonical processing pathway.