Distinct role of CCCTC-binding factor in the differentiation and function of Dendritic cell lineage

Abstract

Dendritic cell (DC) lineage is comprised of heterogeneous subsets of DCs, which could be largely classified by their distinct cytokine dependency for development. CCCTC-binding factor (CTCF) is a genome-wide DNA-binding protein that regulates its target gene expression by controlling the topological structures of chromatin. Previously we demonstrated that CTCF is critically involved in the homeostasis of both epidermal Langerhans cells and hematopoietic stem cells. However, the role of CTCF in other DC lineage development and function remains largely unknown. Here I found that CTCF is not critically required for DCs in the granulocyte macrophage-colony stimulating factor (GM-CSF)-dependent development, unlike for those in the FMS-like tyrosine kinase 3 ligand (Flt3L)-dependent development. Although CTCF was required for optimal bone marrow (BM) progenitor proliferation in both Flt3L-and GM-CSF-supplemented cultures, CTCF-deficient BM and hematopoietic stem cells cultured with GM-CSF showed normal cellular apoptosis rate and higher CD11c+ DC differentiation. GM-CSF-dependent DCs generated from CTCF-deficient BM were demonstrated to drive the enhanced induction of regulatory T cells over Th17 cells in part due to their reduced IL-6 production. IL-6 production in CTCF ablated DCs was affected through NF-kB signaling pathway. According to the experimental autoimmune encephalomyelitis (EAE) model as an autoimmune disease model for Th17, the vaccination of CTCF-deficient DCs showed a prophylactic effect in vivo. My results indicate that CTCF plays a critical role in the production of pro-inflammatory cytokine rather than the development and antigen presentation of GM-CSF-dependent inflammatory DCs. My study demonstrated that targeting CTCF in GM-CSF-dependent inflammatory DCs is a promising new prophylactic modality to control Th17-associated autoimmune diseases.