TGF-beta is required to maintain the pool of immature Langerhans cells in the epidermis

• Published in: The Journal of immunology (1950) 2010-09, Vol.185 (6), p.3248-3255
• Main Authors: Kel, Junda M, Girard-Madoux, Mathilde J H, Reizis, Boris, Clausen, Björn E
• Format: Article
• Language: English
• Subjects: Animals; Cell Differentiation - genetics; Cell Differentiation - immunology; Cell Movement - genetics; Cell Movement - immunology; Cells, Cultured; Dermatitis, Contact - immunology; Dermatitis, Contact - metabolism; Dermatitis, Contact - pathology; Epidermis - cytology; Epidermis - immunology; Epidermis - pathology; Homeostasis - genetics; Homeostasis - immunology; Langerhans Cells - cytology; Langerhans Cells - immunology; Langerhans Cells - pathology; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Protein-Serine-Threonine Kinases - deficiency; Protein-Serine-Threonine Kinases - genetics; Receptors, Transforming Growth Factor beta - deficiency; Receptors, Transforming Growth Factor beta - genetics; Transforming Growth Factor beta1 - physiology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1000981

The pivotal role of TGF-beta in Langerhans cell (LC) development has been previously established in TGF-beta-deficient mice, which lack epidermal LCs. As to whether TGF-beta also governs LC homeostasis and function remains elusive. To assess the role of TGF-beta-mediated control of cutaneous dendritic cells (DCs) in vivo, we generated mice with a conditional knockout of the TGF-beta receptor 1 (TbetaR1) under a DC-specific promoter (DC-TbetaR1(del) mice). While initial LC seeding occurred in DC-TbetaR1(del) mice, the cells disappeared from the epidermis during the first week of life. TbetaR1-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-TbetaR1(del) mice, whereas the number of Langerin(+) dermal DCs was similar to wild-type. In the absence of LCs, low-dose contact hypersensitivity in DC-TbetaR1(del) mice was significantly diminished. In contrast, ear swelling was restored to wild-type levels when a higher hapten dose was applied to efficiently target TbetaR1-deficient dermal DCs. In conclusion, TGF-beta inhibits in vivo LC maturation and migratory phenotype, identifying TGF-beta as a critical factor controlling LC homeostasis in the steady state.