Tuning DO:DM Ratios Modulates MHC Class II Immunopeptidomes.
Tuning DO:DM Ratios Modulates MHC Class II Immunopeptidomes.
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DOI：
10.1016/j.mcpro.2022.100204
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发表时间：
2022-03
影响因子：
7
通讯作者：
Elias, Joshua E.
中科院分区：
文献类型：
--
作者：
Olsson, Niclas;Jiang, Wei;Adler, Lital N.;Mellins, Elizabeth D.;Elias, Joshua E.
主要组织相容性复合体II类（MHC-II）抗原呈递是健康和疾病中广泛免疫应答的基础。然而，MHC-II抗原呈递是如何被肽负载催化剂HLA-DM（DM）及其相关调节剂HLA-DO（DO）调节的还不完全清楚。这在很大程度上是由于技术上的限制：模型抗原呈递细胞（APC）系统，表达这些MHC-II肽组调节剂在生理上可变的水平还没有被描述。同样，计算预测工具，占DO和DM活动目前还没有。为了解决这些差距，我们创建了一组单一的MHC-II等位基因，HLA-DR 4-表达APC线，涵盖了广泛的DO：DM比例状态。使用组合的免疫肽组学和蛋白质组学发现策略，我们通过调查超过10，000种独特的DR 4呈递肽来测量DO：DM比率对肽呈递的影响。由此产生的数据提供了深入了解肽的特点，影响他们的介绍与增加DO：DM比例。这些包括DM敏感性、肽丰度、结合亲和力和基序、肽长度以及沿着源蛋白沿着结合寄存器的选择。这些发现对设计改进的HLA-II预测算法和研究策略以解剖不同APC在体内的各种功能具有影响。具有不同DO：DM比率的新细胞系组通知MHC-II呈递。调整DO：DM比率对应于显著不同的MHC-II免疫肽组。我们的研究填补了理解和预测MHC-II抗原呈递的空白。通过MHC-II的免疫肽呈递调节适应性免疫。非经典MHC分子HLA-DM和HLA-DO协同调节MHC-II功能，并且它们的相对丰度在APC和细胞环境中变化。这种变化如何影响免疫肽库仍不清楚。我们通过建立表达HLA-DM和HLA-DO的细胞系，跨越几个相对丰度并测量其免疫肽库来解决这一问题。我们发现，免疫肽聚类根据他们的介绍水平在不同的DO：DM比例。预测的MHC-II结合亲和力对这些结果有很大贡献，但不能完全解释这些结果。
Major histocompatibility complex class II (MHC-II) antigen presentation underlies a wide range of immune responses in health and disease. However, how MHC-II antigen presentation is regulated by the peptide-loading catalyst HLA-DM (DM), its associated modulator, HLA-DO (DO), is incompletely understood. This is due largely to technical limitations: model antigen-presenting cell (APC) systems that express these MHC-II peptidome regulators at physiologically variable levels have not been described. Likewise, computational prediction tools that account for DO and DM activities are not presently available. To address these gaps, we created a panel of single MHC-II allele, HLA-DR4-expressing APC lines that cover a wide range of DO:DM ratio states. Using a combined immunopeptidomic and proteomic discovery strategy, we measured the effects DO:DM ratios have on peptide presentation by surveying over 10,000 unique DR4-presented peptides. The resulting data provide insight into peptide characteristics that influence their presentation with increasing DO:DM ratios. These include DM sensitivity, peptide abundance, binding affinity and motif, peptide length, and choice of binding register along the source protein. These findings have implications for designing improved HLA-II prediction algorithms and research strategies for dissecting the variety of functions that different APCs serve in the body. A new cell line panel with varied DO:DM ratios informs MHC-II presentation. Tuning DO:DM ratios corresponds with strikingly divergent MHC-II immunopeptidomes. Our study bridges a gap in understanding and predicting MHC-II antigen presentation. Immunopeptide presentation by MHC-II regulates adaptive immunity. The noncanonical MHC molecules HLA-DM and HLA-DO cooperatively regulate MHC-II function, and their relative abundances vary across APCs and cellular contexts. How this variation influences immunopeptide repertoires remains unclear. We addressed this by creating cell lines expressing HLA-DM and HLA-DO, spanning several relative abundances and measuring their immunopeptide repertoires. We found that immunopeptides clustered according to their presentation levels across different DO:DM ratios. Predicted MHC-II binding affinity substantially contributed to but did not fully account for these results.
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影响因子：
46.9
作者：
Hendel A;Bak RO;Clark JT;Kennedy AB;Ryan DE;Roy S;Steinfeld I;Lunstad BD;Kaiser RJ;Wilkens AB;Bacchetta R;Tsalenko A;Dellinger D;Bruhn L;Porteus MH
通讯作者：
Porteus MH
影响因子：
4.4
作者：
Chen, Xinjian;Reed-Loisel, Lisa M.;Jensen, Peter E.
通讯作者：
Jensen, Peter E.
影响因子：
4.4
作者：
Arnold, PY;La Gruta, NL;Vignali, DAA
通讯作者：
Vignali, DAA
影响因子：
15.3
作者：
Glazier, KS;Hake, SB;Denzin, LK
通讯作者：
Denzin, LK
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y