IL-28B is a key regulator of B- and T-cell vaccine responses against influenza

PLoS Pathog. 2014 Dec 11;10(12):e1004556. doi: 10.1371/journal.ppat.1004556. eCollection 2014 Dec.

Abstract

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)-λ 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-γ), 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 α-subunit (IL28RA). In vitro, these peptides significantly suppressed binding of IFN-λs 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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity / drug effects*
  • Adaptive Immunity / immunology
  • Adaptive Immunity / physiology
  • Adult
  • Aged
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / metabolism
  • B-Lymphocytes / pathology*
  • Cell Proliferation
  • Female
  • HLA-DR Antigens / metabolism
  • Humans
  • Immunocompromised Host
  • Immunoglobulin G / metabolism
  • In Vitro Techniques
  • Influenza A Virus, H1N1 Subtype / immunology*
  • Influenza Vaccines / immunology
  • Influenza Vaccines / pharmacology*
  • Influenza, Human / metabolism
  • Influenza, Human / pathology*
  • Influenza, Human / prevention & control
  • Interferons
  • Interleukin-4 / metabolism
  • Interleukins / genetics
  • Interleukins / pharmacology
  • Interleukins / physiology*
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide / genetics
  • Recombinant Proteins / pharmacology
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / pathology*
  • Th1 Cells / pathology
  • Th2 Cells / pathology
  • Transplant Recipients

Substances

  • HLA-DR Antigens
  • IFNL3 protein, human
  • Immunoglobulin G
  • Influenza Vaccines
  • Interleukins
  • Recombinant Proteins
  • Interleukin-4
  • Interferons

Grant support

This work is partly funded by a grant from the Li Ka Shing Institute of Virology. AE research is supported by a salary research grant by the Swiss National Science Foundation (PBBSP3-130963) and a Lichtenstein Foundation grant. AL is supported by the Banting Postdoctoral Fellowship Program, administered by the Government of Canada and by Alberta Innovates Health Solutions Postdoctoral Fellowship, DMS is supported by Canadian Institutes of Health Research and Alberta Innovates Health Solutions Postdoctoral Fellowships, BST is supported by the National CIHR Research Training Program in Hepatitis C (NCRTP-HepC), LFL is supported by a research Fellowship grant from the Canadian Society of Transplantation, MH is supported by the Canada Excellence Research Chair (CERC) in Virology award. DLJT is supported by a grant of the Canadian Institute of Health Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.