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

Anna M. Gram, Chenglong Sun, Sanne L. Landman, Timo Oosenbrug, Hester J. Koppejan, Mark J. Kwakkenbos, Rob C. Hoeben, Søren R. Paludan, Maaike E. Ressing

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)225-237
Number of pages13
JournalMolecular Immunology
Volume91
DOIs
StatePublished - Nov 2017
Externally publishedYes

Keywords

  • cGAS-STING pathway
  • DNA sensing
  • Epstein-Barr virus
  • Human B cells
  • Innate immune signaling
  • Type I interferons

ASJC Scopus subject areas

  • Immunology
  • Molecular Biology

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