TGF-β Is Required To Maintain the Pool of Immature Langerhans Cells in the Epidermis

Abstract

The pivotal role of TGF-β in Langerhans cell (LC) development has been previously established in TGF-β–deficient mice, which lack epidermal LCs. As to whether TGF-β also governs LC homeostasis and function remains elusive. To assess the role of TGF-β–mediated control of cutaneous dendritic cells (DCs) in vivo, we generated mice with a conditional knockout of the TGF-β receptor 1 (TβR1) under a DC-specific promoter (DC-TβR1del mice). While initial LC seeding occurred in DC-TβR1del mice, the cells disappeared from the epidermis during the first week of life. TβR1-deficient LCs demonstrated spontaneous maturation and gained migratory potential based on increased surface expression of MHC class II, costimulatory molecules, and CCR7 and downregulation of E-cadherin. In parallel to their early loss from the epidermis, migrating LCs were reduced in the dermis and skin-draining lymph nodes of adult DC-TβR1del mice, whereas the number of Langerin+ dermal DCs was similar to wild-type. In the absence of LCs, low-dose contact hypersensitivity in DC-TβR1del mice was significantly diminished. In contrast, ear swelling was restored to wild-type levels when a higher hapten dose was applied to efficiently target TβR1-deficient dermal DCs. In conclusion, TGF-β inhibits in vivo LC maturation and migratory phenotype, identifying TGF-β as a critical factor controlling LC homeostasis in the steady state.