ADAM10 shapes myeloid antigen-presenting cell homeostasis in the splenic marginal zone. ADAM10 shapes myeloid antigen-presenting cell homeostasis in the splenic marginal zone

The spleen contains phenotypically and functionally distinct cDC1 and cDC2 subpopulations, which each can be divided into several smaller and less-well characterized subsets. Despite advances in understanding the complexity of DC ontogeny and function by transcriptional programming, the significance of post-translational modifications in controlling tissue-specific cDC (subset) immunobiology remains elusive. Here, we identified the cell surface-expressed A-disintegrin-and-metalloproteinase 10 (ADAM10) as an essential regulator of cDC1 and cDC2 homeostasis in the splenic marginal zone (MZ). Mice with a CD11c-specific deletion of ADAM10 (ADAM10ΔCD11c) exhibited a complete loss of splenic ESAMhi cDC2A, because ADAM10 controlled their commitment, differentiation, survival, and EBI2-mediated localization within the MZ. Moreover, we discovered that ADAM10 is a molecular switch regulating cDC2 subset heterogeneity in the spleen, as this unbalanced cDC2A homeostasis in the absence of ADAM10 was compensated for by the emergence of a novel Clec12a+ cDC2B subset, closely resembling cDC2 generally found in peripheral lymph nodes. Moreover, in ADAM10ΔCD11c mice terminal differentiation of cDC1 was abrogated, resulting in reduced numbers of Langerin+ cDC1. Overall design: Transcriptome analysis of WT and ADAM10-deficient splenic CD4+, CD8+ and CD4-CD8- conventional dendritic cells subsets

脾脏中存在表型与功能均存在差异的常规树突状细胞1型（cDC1）与常规树突状细胞2型（cDC2）亚群，两类亚群均可进一步细分为若干规模更小、特征尚未充分阐明的子集。尽管通过转录编程解析树突状细胞（dendritic cell, DC）发育与功能复杂性的研究已取得诸多进展，但翻译后修饰在调控组织特异性cDC（亚群）免疫生物学特性中的作用仍不明确。本研究鉴定出细胞表面表达的解整合素金属蛋白酶10（A disintegrin and metalloproteinase 10, ADAM10），其可作为脾脏边缘区（splenic marginal zone, MZ）内cDC1与cDC2稳态维持的关键调控因子。CD11c特异性敲除ADAM10的小鼠（ADAM10ΔCD11c）其脾脏内皮细胞选择性黏附分子（endothelial cell-selective adhesion molecule, ESAM）高表达型cDC2A（ESAMhi cDC2A）亚群完全缺失，这是由于ADAM10可调控该亚群的定向分化、存活以及其在边缘区内由EB病毒诱导基因2（Epstein-Barr virus-induced gene 2, EBI2）介导的定位过程。此外，本研究发现ADAM10是调控脾脏内cDC2亚群异质性的分子开关：在ADAM10缺失的情况下，失衡的cDC2A稳态可通过一种新型C型凝集素结构域家族12成员A（C-type lectin domain family 12 member A, Clec12a）阳性（Clec12a+）cDC2B亚群的出现得到代偿，该亚群与外周淋巴结中常见的cDC2表型高度相似。同时，在ADAM10ΔCD11c小鼠体内，cDC1的终末分化过程被阻断，导致朗格素（Langerin）阳性cDC1的数量减少。实验整体设计：对野生型（wild type, WT）与ADAM10缺陷型小鼠的脾脏CD4阳性、CD8阳性以及CD4阴性CD8阴性常规树突状细胞亚群进行转录组分析。