Decoding TGF-beta signaling pathways in skin langerhans cells

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Abstract Langerhans cells (LCs), the skin residing dendritic cells (DCs), control both adaptive immunity and immune tolerance in skin and are involved in the development of a variety of skin diseases. Transforming growth factor-β1 (TGFβ1) is a crucial factor for LC maintenance and function. TGFβ1 signals through interactions with TGFb receptors to activate either Smad-dependent or Smad-independent pathways to regulate TGFb1 target genes and cellular function. However, the signaling pathways, the detailed molecular networks of TGFb1-mediated LC maintenance and functional regulation, and the specific role of TGFb1 and related mechanisms in embryonic LC development remain unclear. Our recent work and preliminary studies showed that TGFb1 is absolutely required for embryonic LC development, in which TGFβ-activated kinase 1 (Tak1), and not Smads, leads the dominant TGFb1 signaling pathway; that Tak1, not Smads, is involved in LC postnatal differentiation; and that Smad signaling pathways are dominant during inflammation- induced LC repopulation. These results strongly suggest that diverse TGFb signaling pathways mediate LC regulations in embryonic ontogeny versus postnatal homeostasis or inflammation- induced repopulation. In the proposed studies, will use different spatial- and temporal-specific and transient inducible gene mutation mouse models combined with RNA-seq, scRNA-seq, ChIP-Seq, imaging FACS, and in vivo/in vitro lentivirus-mediated gene activation and deletion strategies, aiming to decipher the context-dependent specificities of TGFb signaling pathways and related molecular networks that regulate LC ontogeny, postnatal homeostasis, and repopulation. Results from the proposed studies will not only further our understanding of LC biology, but also will shed new light on potential therapeutic targets with high specificity for the treatment of LC-related diseases.