Department of Pediatrics - Human Gene Therapy, Stanford University School of medicine, Stanford, CA, 94305, USA.
Stanford Immunology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
Sci Rep. 2019 Sep 25;9(1):13877. doi: 10.1038/s41598-019-50455-y.
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 DM activity for exchange of placeholder CLIP peptides with high affinity MHCII ligands. Compared to their naïve counterparts, memory B cells with less DM 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 DM activity to optimize antigen presentation for T-cell recruitment.
B 细胞受体和表面展示的肽/MHCII 复合物构成了 B 细胞感应信号的两个关键组件，并在抗原触发激活过程中与其他细胞类型进行通信。然而，协同抗原-BCR 相互作用和抗原肽-MHCII 呈递的关键途径仍难以捉摸。在这里，我们报告了发现参与建立这种协同作用的因素。我们应用了一种单细胞测量方法，并结合超分辨率显微镜，研究了两种溶酶体调节剂 HLA-DM 和 HLA-DO 的肽加载的综合功能。在模型细胞系和人扁桃体 B 细胞中，我们发现可调节的 DM/DO 化学计量学控制着 DM 活性，用于与高亲和力 MHCII 配体交换占位 CLIP 肽。与它们的原始对应物相比，具有较少 DM 的记忆 B 细胞在溶酶体区室中集中了更高比例的 CLIP/MHCII。在由高亲和力 BCR 介导的激活过程中，DO 的调谐与抗原内化同步，并迅速增强 DM 活性，以优化抗原呈递以招募 T 细胞。
