Langerhans cells (LCs) are long-lived, tissue-resident mononuclear phagocytes that form dense networks in stratified epithelia and migrate to draining lymph nodes to maintain immune tolerance. LC development and their immature epithelial identity depend on TGF-β family signaling; however, the transcriptional effectors downstream of this pathway remain incompletely defined. In this study, we identify the basic helix-loop-helix transcription factor BHLHE40 (basic helix-loop-helix E40)/DEC1 (differentially expressed in chondrocytes 1) as a positive regulator of LC lineage commitment and epithelial identity. Transcriptomic profiling of an in vitro LC differentiation system from human hematopoietic progenitors revealed the rapid induction of BHLHE40 downstream of TGF-β1-TGFBR1/ALK5 signaling. Lentiviral knockdown and overexpression demonstrated that BHLHE40 promotes LC differentiation, whereas its loss skews cells toward a monocyte and monocyte-derived dendritic cell fate. The loss of BHLHE40 reduced phosphorylation of SMAD2/3; impaired the expression of RUNX3; and decreased the expression of epithelial markers, including E-cadherin, EpCAM, TROP2, and AXL. In human skin, BHLHE40 is broadly expressed in steady-state LCs but is downregulated in psoriatic LCs. Supporting a conserved role in vivo, Bhlhe40-deficient mice exhibit disruption of the epidermal LC network, whereas LC-specific heterozygous mice show reduced LC accumulation in skin-draining lymph nodes. Together, these findings identify BHLHE40 as a previously unrecognized transcriptional regulator connecting canonical TGF-β1 signaling to epithelial LC homeostasis.
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