The spleen contains phenotypically and functionally distinct conventional dendritic cell (cDC) subpopulations, termed cDC1 and cDC2, which each can be divided into several smaller and less well-characterized subsets. Despite advances in understanding the complexity of cDC ontogeny by transcriptional programming, the significance of posttranslational 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 (ADAM10^ΔCD11c) exhibited a complete loss of splenic ESAM^hi cDC2A because ADAM10 regulated the commitment, differentiation, and survival of these cells. The major pathways controlled by ADAM10 in ESAM^hi cDC2A are Notch, signaling pathways involved in cell proliferation and survival (e.g., mTOR, PI3K/AKT, and EIF2 signaling), and EBI2-mediated localization within the MZ. In addition, we discovered that ADAM10 is a molecular switch regulating cDC2 subset heterogeneity in the spleen, as the disappearance of ESAM^hi cDC2A in ADAM10^ΔCD11c mice was compensated for by the emergence of a Clec12a⁺ cDC2B subset closely resembling cDC2 generally found in peripheral lymph nodes. Moreover, in ADAM10^ΔCD11c mice, terminal differentiation of cDC1 was abrogated, resulting in severely reduced splenic Langerin⁺ cDC1 numbers. Next to the disturbed splenic cDC compartment, ADAM10 deficiency on CD11c⁺ cells led to an increase in marginal metallophilic macrophage (MMM) numbers. In conclusion, our data identify ADAM10 as a molecular hub on both cDC and MMM regulating their transcriptional programming, turnover, homeostasis, and ability to shape the anatomical niche of the MZ.

脾脏包含表型和功能上不同的常规树突状细胞 (cDC) 亚群，称为 cDC1 和 cDC2，每个亚群都可以分为几个较小且特征较少的亚群。尽管通过转录编程在理解 cDC 个体发育的复杂性方面取得了进展，但翻译后修饰在控制组织特异性 cDC 子集免疫生物学中的重要性仍然难以捉摸。在这里，我们将细胞表面表达的 A-去整合素和金属蛋白酶 10 (ADAM10) 鉴定为脾边缘区 (MZ) 中 cDC1 和 cDC2 稳态的重要调节剂。CD11c 特异性缺失 ADAM10 (ADAM10 ^ΔCD11c ) 的小鼠表现出脾脏 ESAM ^{hi完全丧失}cDC2A，因为 ADAM10 调节这些细胞的承诺、分化和存活。ESAM ^hi cDC2A 中由 ADAM10 控制的主要途径是 Notch、参与细胞增殖和存活的信号传导途径（例如，mTOR、PI3K/AKT 和 EIF2 信号传导）和 EBI2 介导的 MZ 内定位。此外，我们发现 ADAM10 是调节脾脏中 cDC2 亚群异质性的分子开关，因为在 ADAM10 ^{ΔCD11c小鼠中 ESAM hi} cDC2A的消失被一个与外周淋巴中常见的 cDC2 非常相似的 Clec12a ⁺ cDC2B 亚群的出现所补偿节点。此外，在 ADAM10 ^ΔCD11c在小鼠中，cDC1 的终末分化被消除，导致脾脏Langerin ⁺ cDC1 数量严重减少。在受干扰的脾 cDC 隔室旁边，CD11c ⁺细胞上的 ADAM10 缺乏导致边缘嗜金属巨噬细胞 (MMM) 数量增加。总之，我们的数据将 ADAM10 确定为 cDC 和 MMM 的分子中心，调节它们的转录编程、周转、稳态和塑造 MZ 解剖生态位的能力。