Dicer-dependent microRNAs control maturation, function, and maintenance of Langerhans cells in vivo.
Dendritic cells (DCs) are central for the induction of T cell immunity and tolerance. Fundamental for DCs to control the immune system is their differentiation from precursors into various DC subsets with distinct functions and locations in lymphoid organs and tissues. In contrast to the differentiation of epidermal Langerhans cells (LCs) and their seeding into the epidermis, LC maturation, turnover, and MHC class II Ag presentation capacities are strictly dependent on the presence of Dicer, which generates mature microRNAs (miRNAs). Absence of miRNAs caused a strongly disturbed steady-state homeostasis of LCs by increasing their turnover and apoptosis rate, leading to progressive ablation of LCs with age. The failure to maintain LCs populating the epidermis was accompanied by a proapoptotic gene expression signature. Dicer-deficient LCs showed largely increased cell sizes and reduced expression levels of the C-type lectin receptor Langerin, resulting in the lack of Birbeck granules. In addition, LCs failed to properly upregulate MHC class II, CD40, and CD86 surface molecules upon stimulation, which are critical hallmarks of functional DC maturation. This resulted in inefficient induction of CD4 T cell proliferation, whereas Dicer-deficient LCs could properly stimulate CD8 T cells. Taken together, Dicer-dependent generation of miRNAs affects homeostasis and function of epidermal LCs.
Institute for Immunology, Ludwig-Maximilian-University Munich, Munich, Germany.
Harmjan
H
Kuipers
Frauke M
FM
Schnorfeil
Hans-Jörg
HJ
Fehling
Helmut
H
Bartels
Thomas
T
Brocker
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics* / Q000276:immunology*; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D053487:DEAD-box RNA Helicases / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D003877:Dermatitis, Contact / Q000235:genetics / Q000276:immunology / Q000473:pathology; D004722:Endoribonucleases / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D005786:Gene Expression Regulation / Q000276:immunology; D006706:Homeostasis / Q000235:genetics / Q000276:immunology; D007801:Langerhans Cells / Q000166:cytology* / Q000276:immunology* / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D043244:Ribonuclease III
D035683:MicroRNAs; D004722:Endoribonucleases; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases