Impact of human sepsis on CCCTC-binding factor associated monocyte transcriptional response of Major Histocompatibility Complex II components

PLoS One. 2018 Sep 13;13(9):e0204168. doi: 10.1371/journal.pone.0204168. eCollection 2018.


Background: Antigen presentation on monocyte surface to T-cells by Major Histocompatibility Complex, Class II (MHC-II) molecules is fundamental for pathogen recognition and efficient host response. Accordingly, loss of Major Histocompatibility Complex, Class II, DR (HLA-DR) surface expression indicates impaired monocyte functionality in patients suffering from sepsis-induced immunosuppression. Besides the impact of Class II Major Histocompatibility Complex Transactivator (CIITA) on MHC-II gene expression, X box-like (XL) sequences have been proposed as further regulatory elements. These elements are bound by the DNA-binding protein CCCTC-Binding Factor (CTCF), a superordinate modulator of gene transcription. Here, we hypothesized a differential interaction of CTCF with the MHC-II locus contributing to an altered monocyte response in immunocompromised septic patients.

Methods: We collected blood from six patients diagnosed with sepsis and six healthy controls. Flow cytometric analysis was used to identify sepsis-induced immune suppression, while inflammatory cytokine levels in blood were determined via ELISA. Isolation of CD14++ CD16-monocytes was followed by (i) RNA extraction for gene expression analysis and (ii) chromatin immunoprecipitation to assess the distribution of CTCF and chromatin modifications in selected MHC-II regions.

Results: Compared to healthy controls, CD14++ CD16-monocytes from septic patients with immune suppression displayed an increased binding of CTCF within the MHC-II locus combined with decreased transcription of CIITA gene. In detail, enhanced CTCF enrichment was detected on the intergenic sequence XL9 separating two subregions coding for MHC-II genes. Depending on the relative localisation to XL9, gene expression of both regions was differentially affected in patients with sepsis.

Conclusion: Our experiments demonstrate for the first time that differential CTCF binding at XL9 is accompanied by uncoupled MHC-II expression as well as transcriptional and epigenetic alterations of the MHC-II regulator CIITA in septic patients. Overall, our findings indicate a sepsis-induced enhancer blockade mediated by variation of CTCF at the intergenic sequence XL9 in altered monocytes during immunosuppression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antigen Presentation
  • Base Sequence
  • CCCTC-Binding Factor / genetics
  • CCCTC-Binding Factor / immunology*
  • Case-Control Studies
  • Chromatin / chemistry
  • Chromatin / immunology
  • DNA, Intergenic / genetics
  • DNA, Intergenic / immunology*
  • Female
  • GPI-Linked Proteins / deficiency
  • GPI-Linked Proteins / genetics
  • GPI-Linked Proteins / immunology
  • Gene Expression Regulation
  • Genetic Loci
  • Histocompatibility Antigens Class II / genetics
  • Histocompatibility Antigens Class II / immunology*
  • Humans
  • Immunocompromised Host*
  • Lipopolysaccharide Receptors / genetics
  • Lipopolysaccharide Receptors / immunology
  • Male
  • Monocytes / immunology
  • Monocytes / pathology
  • Nuclear Proteins / genetics
  • Nuclear Proteins / immunology
  • Protein Binding
  • Receptors, IgG / deficiency
  • Receptors, IgG / genetics
  • Receptors, IgG / immunology
  • Regulatory Elements, Transcriptional
  • Sepsis / genetics
  • Sepsis / immunology*
  • Sepsis / pathology
  • Signal Transduction
  • T-Lymphocytes / immunology
  • T-Lymphocytes / pathology
  • Trans-Activators / genetics
  • Trans-Activators / immunology
  • Transcription, Genetic


  • CCCTC-Binding Factor
  • CTCF protein, human
  • Chromatin
  • DNA, Intergenic
  • FCGR3B protein, human
  • GPI-Linked Proteins
  • Histocompatibility Antigens Class II
  • Lipopolysaccharide Receptors
  • MHC class II transactivator protein
  • Nuclear Proteins
  • Receptors, IgG
  • Trans-Activators

Grants and funding

We acknowledge financial support by Deutsche Forschungsgemeinschaft within the funding programme Open Access Publishing, by the Baden-Württemberg Ministry of Science, Research and the Arts and by Ruprecht-Karls-Universität Heidelberg. This work was supported by the German Centre for Infection Research (DZIF, DZIFZN2013,<>). The funders had no role in study design, collection, analysis, and interpretation of data, decision to publish or writing the manuscript.