Human B cells fail to secrete type I interferons upon cytoplasmic DNA exposure

Mol Immunol. 2017 Nov;91:225-237. doi: 10.1016/j.molimm.2017.08.025. Epub 2017 Sep 30.

Abstract

Most cells are believed to be capable of producing type I interferons (IFN I) as part of an innate immune response against, for instance, viral infections. In macrophages, IFN I is potently induced upon cytoplasmic exposure to foreign nucleic acids. Infection of these cells with herpesviruses leads to triggering of the DNA sensors interferon-inducible protein 16 (IFI16) and cyclic GMP-AMP (cGAMP) synthase (cGAS). Thereby, the stimulator of interferon genes (STING) and the downstream molecules TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3) are sequentially activated culminating in IFN I secretion. Human gamma-herpesviruses, such as Epstein-Barr virus (EBV), exploit B cells as a reservoir for persistent infection. In this study, we investigated whether human B cells, similar to macrophages, engage the cytoplasmic DNA sensing pathway to induce an innate immune response. We found that the B cells fail to secrete IFN I upon cytoplasmic DNA exposure, although they express the DNA sensors cGAS and IFI16 and the signaling components TBK1 and IRF3. In primary human B lymphocytes and EBV-negative B cell lines, this deficiency is explained by a lack of detectable levels of the central adaptor protein STING. In contrast, EBV-transformed B cell lines did express STING, yet both these lines as well as STING-reconstituted EBV-negative B cells did not produce IFN I upon dsDNA or cGAMP stimulation. Our combined data show that the cytoplasmic DNA sensing pathway is dysfunctional in human B cells. This exemplifies that certain cell types cannot induce IFN I in response to cytoplasmic DNA exposure providing a potential niche for viral persistence.

Keywords: DNA sensing; Epstein-Barr virus; Human B cells; Innate immune signaling; Type I interferons; cGAS-STING pathway.

MeSH terms

  • B-Lymphocytes / immunology*
  • B-Lymphocytes / metabolism
  • B-Lymphocytes / pathology
  • Cell Line, Transformed
  • DNA / immunology*
  • DNA / metabolism
  • Epstein-Barr Virus Infections / immunology
  • Epstein-Barr Virus Infections / metabolism
  • Epstein-Barr Virus Infections / pathology
  • Female
  • Herpesvirus 4, Human / immunology
  • Humans
  • Interferon Regulatory Factor-3 / immunology
  • Interferon Regulatory Factor-3 / metabolism
  • Interferon Type I / immunology*
  • Interferon Type I / metabolism
  • Male
  • Membrane Proteins / immunology
  • Membrane Proteins / metabolism
  • Nuclear Proteins / immunology
  • Nuclear Proteins / metabolism
  • Nucleotidyltransferases / immunology
  • Nucleotidyltransferases / metabolism
  • Phosphoproteins / immunology
  • Phosphoproteins / metabolism
  • Protein-Serine-Threonine Kinases / immunology
  • Protein-Serine-Threonine Kinases / metabolism

Substances

  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • Interferon Type I
  • Membrane Proteins
  • Nuclear Proteins
  • Phosphoproteins
  • STING protein, human
  • IFI16 protein, human
  • DNA
  • Protein-Serine-Threonine Kinases
  • TBK1 protein, human
  • MB21D1 protein, human
  • Nucleotidyltransferases