Synergy between B cell receptor/antigen uptake and MHCII peptide editing relies on HLA-DO tuning
Synergy between B cell receptor/antigen uptake and MHCII peptide editing relies on HLA-DO tuning
复制标题
DOI：
10.1038/s41598-019-50455-y
复制
发表时间：
2019-09-25
影响因子：
4.6
通讯作者：
Mellins, Elizabeth D.
中科院分区：
文献类型：
--
作者：
Jiang, Wei;Adler, Lital N.;Mellins, Elizabeth D.
B细胞受体和表面展示肽/MHCII复合物构成B细胞机制的两个关键组分，以在抗原触发的活化期间感测信号并与其它细胞类型通信。然而，协同抗原-BCR相互作用和抗原肽-MHCII呈递的关键途径仍然难以捉摸。在这里，我们报告发现的因素参与建立这种协同作用。我们应用单细胞测量结合超分辨率显微镜来研究两个溶酶体调节肽装载的整合功能，HLA-DM和HLA-DO。在模型细胞系和人扁桃体B细胞中，我们发现可调的DM/DO化学计量比支配用于占位符CLIP肽与高亲和力MHCII配体交换的无DM活性。与它们的幼稚对应物相比，具有较少无DM的记忆B细胞在溶酶体隔室中浓缩较高比例的CLIP/MHCII。在由高亲和力BCR介导的活化后，DO调节与抗原内化同步，并快速增强无DM活性以优化用于T细胞募集的抗原呈递。
B cell receptors and surface-displayed peptide/MHCII complexes constitute two key components of the B-cell machinery to sense signals and communicate with other cell types during antigen-triggered activation. However, critical pathways synergizing antigen-BCR interaction and antigenic peptide-MHCII presentation remain elusive. Here, we report the discovery of factors involved in establishing such synergy. We applied a single-cell measure coupled with super-resolution microscopy to investigate the integrated function of two lysosomal regulators for peptide loading, HLA-DM and HLA-DO. In model cell lines and human tonsillar B cells, we found that tunable DM/DO stoichiometry governs DMfree activity for exchange of placeholder CLIP peptides with high affinity MHCII ligands. Compared to their naive counterparts, memory B cells with less DMfree concentrate a higher proportion of CLIP/MHCII in lysosomal compartments. Upon activation mediated by high affinity BCR, DO tuning is synchronized with antigen internalization and rapidly potentiates DMfree activity to optimize antigen presentation for T-cell recruitment.