As the largest organ of the human body, the skin functions as the primary immunological interface with the external environment, forming the first line of defense in the body's immune barrier [1]. Langerhans cells (LCs), which account for 3%–4% of epidermal cells and exhibit a slight decrease in abundance in the elderly, serve as potent antigen-presenting cells (APCs) within the epidermis [2]. LCs efficiently process epidermal antigens, migrate to local draining lymph nodes, and initiate adaptive immune responses through antigen presentation 1, 3•.

LCs are primarily identified by CD1a, HLA-DR, and langerin (CD207) in humans. CD1a presents microbial lipid antigens to T cells, similar to the role of CD1d in mice [4]. HLA-DR is an MHC class II cell surface receptor that serves as a ligand for the T-cell receptor [5]. Langerin is a lectin receptor that mediates pathogen endocytosis and forms Birbeck granules (BG), which are unique organelles specific to LCs [6]. Langerin is highly expressed on LCs and certain dermal dendritic cells 7, 8, which contributes to the recognition of LCs as a distinct subset of DCs. Furthermore, LCs express EpCAM (CD326), E-Cadherin, and exhibit low expression of DEC-205 (CD205), all of which are involved in cell adhesion and antigen capture process [9]. In mouse models, LCs are typically identified by markers, such as CD11b, MHC-Ⅱ, CD207, and EpCAM. CD103 and EpCAM are used to distinguish langerin+ DCs from LCs, as skin langerin+ DCs express CD103, while LCs and other dermal DC populations lack this marker [10]. Additionally, LCs exhibit significantly higher levels of CD11b and EpCAM compared to skin langerin+ DCs [11].

Ontogenetically, two distinct LC populations have been identified: embryonically derived LCs, originating from yolk sac macrophages, colonize the epidermis and self-renew to maintain homeostatic population levels [12], and monocyte-derived LCs (moLCs) generating from circulating Gr-1hi monocytes migrate to skin-draining lymph nodes [13] or repopulate the epidermis under inflammatory conditions [14]. Recent single-cell sequencing studies have further categorized human skin LCs into four distinct subsets: steady-state LCs, including CD207+CD1a+ LC1 subset with self-renewal capacity, CD207loCD1c+CD1b+ LC2 subset with enhanced migratory ability but reduced viability; and CD207loCD1aloCCR7+ LCs (which correspond to activated LCs and migrated LCs) [15]. Notably, despite emerging evidence highlighting the divergent roles of LC subsets in disease pathogenesis, our understanding of their functional heterogeneity in pathological contexts remains limited.