Langerhans cells (LCs) play a pivotal role in skin homeostasis, and the heterogeneity of LCs has long been considered. In this study, we have identified two steady-state (LC1 and LC2) and two activated LC subsets in the epidermis of human skin and in LCs derived from CD34⁺ hemopoietic stem cells (HSC-LCs) by utilizing single-cell RNA sequencing and mass cytometry. Analysis of HSC-LCs at multiple time-points during differentiation revealed that EGR1 and Notch signaling were among the top pathways regulating the bifurcation of LC1 and LC2. LC1 were characterized as classical LCs, mainly related to innate immunity and antigen processing. LC2 were similar to monocytes or myeloid dendritic cells, involving in immune responses and leukocyte activation. LC1 remained stable under inflammatory microenvironment, whereas LC2 were prone to being activated and demonstrated elevated expression of immuno-suppressive molecules. We revealed distinct human LC subsets that require different developmental regulation and orchestrate reciprocal functions.

朗格汉斯细胞 (LC) 在皮肤稳态中起着关键作用，长期以来人们一直在考虑 LC 的异质性。^{在这项研究中，我们在人类皮肤表皮和源自 CD34 +}的 LC 中确定了两个稳态（LC1 和 LC2）和两个激活的 LC 子集利用单细胞 RNA 测序和质谱细胞术检测造血干细胞 (HSC-LC)。在分化过程中多个时间点对 HSC-LC 的分析表明，EGR1 和 Notch 信号是调节 LC1 和 LC2 分叉的主要途径之一。LC1被表征为经典LC，主要与先天免疫和抗原加工有关。LC2 类似于单核细胞或髓样树突状细胞，参与免疫反应和白细胞活化。LC1 在炎症微环境下保持稳定，而 LC2 易于被激活并表现出免疫抑制分子的表达升高。我们揭示了不同的人类 LC 子集，这些子集需要不同的发育调节和协调相互功能。