TGF-beta is required to maintain the pool of immature Langerhans cells in the epidermis.
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.
Kel
Junda M
JM
Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
Girard-Madoux
Mathilde J H
MJ
Reizis
Boris
B
Clausen
Björn E
BE
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D003877:Dermatitis, Contact / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000078404:Epidermal Cells; D004817:Epidermis / Q000276:immunology* / Q000473:pathology; D006706:Homeostasis / Q000235:genetics / Q000276:immunology; D007801:Langerhans Cells / Q000166:cytology* / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000172:deficiency / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000502:physiology*
D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I