CCCTC-binding factor controls the homeostatic maintenance and migration of Langerhans cells.
BACKGROUND
Langerhans cells (LCs) are skin-resident dendritic cells (DCs) that orchestrate skin immunity. CCCTC-binding factor (CTCF) is a highly conserved DNA-binding protein that regulates higher-order chromatin organization and is involved in various gene regulation processes.


OBJECTIVE
We sought to clarify a possible role for CTCF in LC homeostasis and function in vivo.


METHODS
We used a conditional gene deletion mouse system to generate DC- and LC-specific CTCF-ablated mice. Short hairpin RNA-mediated RNA interference was used to silence CTCF expression in human monocyte-derived Langerhans cells. DC populations were assessed by using flow cytometry and immunofluorescence. Gene expression arrays were performed to identify genes regulated by CTCF in LCs. Contact hypersensitivity and epicutaneous sensitization responses were measured to examine the functional significance of CTCF ablation.


RESULTS
DC-specific CTCF deletion led to a reduced pool of systemic DCs, with LCs most severely affected. Decreases in epidermal LC numbers were specifically associated with self-turnover defects. Interestingly, CTCF-deficient LCs demonstrated impaired migration out of the epidermis. Whole-transcriptome analyses revealed that genes that promoted cell adhesion were highly expressed, but CCR7 was downregulated in CTCF-depleted LCs. Hapten-induced contact hypersensitivity responses were more sustained in LC-specific CTCF-deficient mice, whereas epicutaneous sensitization to protein antigen was attenuated, indicating that CTCF-dependent LC homeostasis is required for optimal immune function of LCs in a context-dependent manner.


CONCLUSIONS
Our results show that CTCF positively regulates the homeostatic pool and the efficient emigration of LCs, which are required for modulating the functional immune network of the skin.
Department of Environmental Medical Biology, Institute of Tropical Medicine, Yonsei University College of Medicine, Seoul, Korea; Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
Tae-Gyun
TG
Kim
Department of Environmental Medical Biology, Institute of Tropical Medicine, Yonsei University College of Medicine, Seoul, Korea.
Mikyoung
M
Kim
Department of Environmental Medical Biology, Institute of Tropical Medicine, Yonsei University College of Medicine, Seoul, Korea; Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
Jong-Joo
JJ
Lee
Department of Dermatology, Yonsei University College of Medicine, Seoul, Korea.
Sung Hee
SH
Kim
Department of Dermatology, Yonsei University College of Medicine, Seoul, Korea.
Jeong Hwan
JH
Je
Department of Integrated OMICS for Biomedical Science, Graduate School, Yonsei University, Seoul, Korea.
Yangsin
Y
Lee
Department of Environmental Medical Biology, Institute of Tropical Medicine, Yonsei University College of Medicine, Seoul, Korea.
Min-Ji
MJ
Song
Department of Environmental Medical Biology, Institute of Tropical Medicine, Yonsei University College of Medicine, Seoul, Korea; Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
Yeeun
Y
Choi
Department of Environmental Medical Biology, Institute of Tropical Medicine, Yonsei University College of Medicine, Seoul, Korea.
Youn Wook
YW
Chung
Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea; Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea.
Chae Gyu
CG
Park
Department of Integrated OMICS for Biomedical Science, Graduate School, Yonsei University, Seoul, Korea.
Jin Won
JW
Cho
Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea; Department of Dermatology, Yonsei University College of Medicine, Seoul, Korea.
Min-Geol
MG
Lee
Cancer Genomics Branch, National Cancer Center, Goyang, Korea.
Yeon-Su
YS
Lee
Department of Environmental Medical Biology, Institute of Tropical Medicine, Yonsei University College of Medicine, Seoul, Korea; Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea. Electronic address: kimhp@yuhs.ac.
Hyoung-Pyo
HP
Kim
D000818:Animals; D000076246:CCCTC-Binding Factor; D002448:Cell Adhesion; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D003877:Dermatitis, Contact / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D004817:Epidermis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006241:Haptens; D006706:Homeostasis / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007801:Langerhans Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D034741:RNA, Small Interfering / Q000235:genetics / Q000276:immunology; D054400:Receptors, CCR7 / Q000235:genetics / Q000276:immunology; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction
D000076246:CCCTC-Binding Factor; C515370:CCR7 protein, human; C000619697:CTCF protein, human; C000619698:Ctcf protein, mouse; D006241:Haptens; D034741:RNA, Small Interfering; D054400:Receptors, CCR7; D012097:Repressor Proteins
CCCTC-binding factor; Langerhans cells; dendritic cells; homeostasis; immune modulation; migration