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

Tae 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, Mingeol Lee, Yeon Su Lee, Hyoung Pyo Kim

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

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. 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.

Original languageEnglish
Pages (from-to)713-724
Number of pages12
JournalJournal of Allergy and Clinical Immunology
Volume136
Issue number3
DOIs
Publication statusPublished - 2015 Sep 1

Fingerprint

Langerhans Cells
Maintenance
Dendritic Cells
Contact Dermatitis
CCCTC-binding factor
Homeostasis
Genes
Skin
Haptens
Emigration and Immigration
Gene Deletion
DNA-Binding Proteins
Gene Expression Profiling
RNA Interference
Epidermis
Cell Adhesion
Small Interfering RNA
Chromatin
Fluorescent Antibody Technique
Monocytes

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Kim, Tae Gyun ; Kim, Mikyoung ; Lee, Jong Joo ; Kim, Sung Hee ; Je, Jeong Hwan ; Lee, Yangsin ; Song, Min Ji ; Choi, Yeeun ; Chung, Youn Wook ; Park, Chae Gyu ; Cho, Jin Won ; Lee, Mingeol ; Lee, Yeon Su ; Kim, Hyoung Pyo. / CCCTC-binding factor controls the homeostatic maintenance and migration of Langerhans cells. In: Journal of Allergy and Clinical Immunology. 2015 ; Vol. 136, No. 3. pp. 713-724.
@article{13018d504c484ef3a51069cb1c952a2f,
title = "CCCTC-binding factor controls the homeostatic maintenance and migration of Langerhans cells",
abstract = "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. 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.",
author = "Kim, {Tae Gyun} and Mikyoung Kim and Lee, {Jong Joo} and Kim, {Sung Hee} and Je, {Jeong Hwan} and Yangsin Lee and Song, {Min Ji} and Yeeun Choi and Chung, {Youn Wook} and Park, {Chae Gyu} and Cho, {Jin Won} and Mingeol Lee and Lee, {Yeon Su} and Kim, {Hyoung Pyo}",
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doi = "10.1016/j.jaci.2015.03.033",
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Kim, TG, Kim, M, Lee, JJ, Kim, SH, Je, JH, Lee, Y, Song, MJ, Choi, Y, Chung, YW, Park, CG, Cho, JW, Lee, M, Lee, YS & Kim, HP 2015, 'CCCTC-binding factor controls the homeostatic maintenance and migration of Langerhans cells', Journal of Allergy and Clinical Immunology, vol. 136, no. 3, pp. 713-724. https://doi.org/10.1016/j.jaci.2015.03.033

CCCTC-binding factor controls the homeostatic maintenance and migration of Langerhans cells. / Kim, Tae Gyun; Kim, Mikyoung; Lee, Jong Joo; Kim, Sung Hee; Je, Jeong Hwan; Lee, Yangsin; Song, Min Ji; Choi, Yeeun; Chung, Youn Wook; Park, Chae Gyu; Cho, Jin Won; Lee, Mingeol; Lee, Yeon Su; Kim, Hyoung Pyo.

In: Journal of Allergy and Clinical Immunology, Vol. 136, No. 3, 01.09.2015, p. 713-724.

Research output: Contribution to journalArticle

TY - JOUR

T1 - CCCTC-binding factor controls the homeostatic maintenance and migration of Langerhans cells

AU - Kim, Tae Gyun

AU - Kim, Mikyoung

AU - Lee, Jong Joo

AU - Kim, Sung Hee

AU - Je, Jeong Hwan

AU - Lee, Yangsin

AU - Song, Min Ji

AU - Choi, Yeeun

AU - Chung, Youn Wook

AU - Park, Chae Gyu

AU - Cho, Jin Won

AU - Lee, Mingeol

AU - Lee, Yeon Su

AU - Kim, Hyoung Pyo

PY - 2015/9/1

Y1 - 2015/9/1

N2 - 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. 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.

AB - 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. 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.

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