Journal
PLOS PATHOGENS
Volume 10, Issue 12, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.ppat.1004556
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Funding
- Li Ka Shing Institute of Virology
- Swiss National Science Foundation [PBBSP3-130963]
- Lichtenstein Foundation
- Banting Postdoctoral Fellowship Program
- Alberta Innovates Health Solutions Postdoctoral Fellowship
- Canadian Institutes of Health Research
- Alberta Innovates Health Solutions Postdoctoral Fellowships
- National CIHR Research Training Program in Hepatitis C (NCRTP-HepC)
- Canadian Society of Transplantation
- Canada Excellence Research Chair (CERC) in Virology award
- Canadian Institute of Health Research
- Swiss National Science Foundation (SNF) [PBBSP3-130963] Funding Source: Swiss National Science Foundation (SNF)
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Influenza is a major cause of morbidity and mortality in immunosuppressed persons, and vaccination often confers insufficient protection. IL-28B, a member of the interferon (IFN)-lambda family, has variable expression due to single nucleotide polymorphisms (SNPs). While type-I IFNs are well known to modulate adaptive immunity, the impact of IL-28B on B- and T-cell vaccine responses is unclear. Here we demonstrate that the presence of the IL-28B TG/GG genotype (rs8099917, minor-allele) was associated with increased seroconversion following influenza vaccination (OR 1.99 p = 0.038). Also, influenza A (H1N1)-stimulated T- and B-cells from minor-allele carriers showed increased IL-4 production (4-fold) and HLA-DR expression, respectively. In vitro, recombinant IL-28B increased Th1-cytokines (e.g. IFN-gamma), and suppressed Th2-cytokines (e.g. IL-4, IL-5, and IL-13), H1N1-stimulated B-cell proliferation (reduced 70%), and IgG-production (reduced>70%). Since IL-28B inhibited B-cell responses, we designed antagonistic peptides to block the IL-28 receptor alpha-subunit (IL28RA). In vitro, these peptides significantly suppressed binding of IFN-lambda s to IL28RA, increased H1N1-stimulated B-cell activation and IgG-production in samples from healthy volunteers (2-fold) and from transplant patients previously unresponsive to vaccination (1.4-fold). Together, these findings identify IL-28B as a key regulator of the Th1/Th2 balance during influenza vaccination. Blockade of IL28RA offers a novel strategy to augment vaccine responses.
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