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.
Bibliographical noteFunding Information:
Supported by National Research Foundation of Korea (NRF) grants funded by the Korean government (MSIP; NRF-2011-0030086 , 2012M3A9B4028272 , and NRF-2013R1A1A2008812 to H.P.-K. and NRF-2013R1A2A1A01008067 to J.W.C.).
Disclosure of potential conflict of interest: H.-P. Kim has received research support from the National Research Foundation of Korea ( NRF-2011-0030086 , 2012M3A9B4028272 , and NRF-2013R1A1A2008812 ) and has a pending patent through Yonsei University Office of Research Affairs and University-Industry Foundation (UIF). The rest of the authors declare that they have no relevant conflicts of interest.
© 2015 American Academy of Allergy, Asthma & Immunology.
All Science Journal Classification (ASJC) codes
- Immunology and Allergy