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CCCTC-binding factor controls the homeostatic maintenance and migration of Langerhans cells.

AbstractBACKGROUND:
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.
CONCLUSION:
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.
AuthorsTae-Gyun Kim, Mikyoung Kim, Jong-Joo Lee, Sung Hee Kim, Jeong Hwan Je, Yangsin Lee, Min-Ji Song, Yeeun Choi, Youn Wook Chung, Chae Gyu Park, Jin Won Cho, Min-Geol Lee, Yeon-Su Lee, Hyoung-Pyo Kim
JournalThe Journal of allergy and clinical immunology (J Allergy Clin Immunol) Vol. 136 Issue 3 Pg. 713-24 (Sep 2015) ISSN: 1097-6825 [Electronic] United States
PMID25936568 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Chemical References
  • CCCTC-Binding Factor
  • CCR7 protein, human
  • CTCF protein, human
  • Ctcf protein, mouse
  • Haptens
  • RNA, Small Interfering
  • Receptors, CCR7
  • Repressor Proteins
Topics
  • Animals
  • CCCTC-Binding Factor
  • Cell Adhesion
  • Cell Movement (genetics, immunology)
  • Dermatitis, Contact (genetics, immunology, pathology)
  • Epidermis (immunology, metabolism, pathology)
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Haptens
  • Homeostasis (genetics, immunology)
  • Humans
  • Langerhans Cells (immunology, metabolism, pathology)
  • Mice
  • Mice, Knockout
  • RNA, Small Interfering (genetics, immunology)
  • Receptors, CCR7 (genetics, immunology)
  • Repressor Proteins (antagonists & inhibitors, deficiency, genetics, immunology)
  • Signal Transduction

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