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.
Adrian Egli  1 ,  Deanna M Santer  2 ,  Daire O'Shea  3 ,  Khaled Barakat  4 ,  Mohammedyaseen Syedbasha  5 ,  Madeleine Vollmer  5 ,  Aliyah Baluch  6 ,  Rakesh Bhat  2 ,  Jody Groenendyk  7 ,  Michael A Joyce  2 ,  Luiz F Lisboa  2 ,  Brad S Thomas  2 ,  Manuel Battegay  8 ,  Nina Khanna  8 ,  Thomas Mueller  9 ,  D Lorne J Tyrrell  2 ,  Michael Houghton  2 ,  Atul Humar  10 ,  Deepali Kumar  10
Affiliations
  • 1. Infection Biology, Department of Biomedicine, University of Basel, Basel, Switzerland; Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada.
  • 2. Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada.
  • 3. Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada; Division of Infectious Diseases, University of Alberta, Edmonton, Alberta, Canada.
  • 4. Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada; Faculty of Pharmacy, University of Alberta, Canada.
  • 5. Infection Biology, Department of Biomedicine, University of Basel, Basel, Switzerland.
  • 6. Division of Infectious Diseases, Moffitt Cancer Center, Tampa, Florida, United States of America.
  • 7. Department of Biochemistry, School of Translational Medicine, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada.
  • 8. Infection Biology, Department of Biomedicine, University of Basel, Basel, Switzerland; Division of Infectious Diseases and Hospital Epidemiology, University Hospital of Basel, Switzerland.
  • 9. Division of Nephrology, University Hospital of Zurich, Zurich, Switzerland.
  • 10. Department of Medicine and Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada.
PMID: 25503988 DOI: 10.1371/journal.ppat.1004556
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.

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