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

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

Author information

1
Department Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: a.m.gram@lumc.nl.
2
Department of Biomedicine, University of Aarhus, Aarhus, Denmark. Electronic address: chenglongsun@biomed.au.dk.
3
Department Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: s.l.landman@lumc.nl.
4
Department Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: t.oosenbrug@lumc.nl.
5
Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: h.j.koppejan@lumc.nl.
6
AIMM Therapeutics b.v., Amsterdam, The Netherlands. Electronic address: mjkwakkenbos@aimmtherapeutics.com.
7
Department Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: r.c.hoeben@lumc.nl.
8
Department of Biomedicine, University of Aarhus, Aarhus, Denmark. Electronic address: srp@biomed.au.dk.
9
Department Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: m.e.ressing@lumc.nl.

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

PMID:
28968560
DOI:
10.1016/j.molimm.2017.08.025
[Indexed for MEDLINE]
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