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

Adrian Egli; Deanna M Santer; Daire O'Shea; Khaled Barakat; Mohammedyaseen Syedbasha; Madeleine Vollmer; Aliyah Baluch; Rakesh Bhat; Jody Groenendyk; Michael A Joyce; Luiz F Lisboa; Brad S Thomas; Manuel Battegay; Nina Khanna; Thomas Mueller; D Lorne J Tyrrell; Michael Houghton; Atul Humar; Deepali Kumar

doi:10.1371/journal.ppat.1004556

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.

Authors

Adrian Egli¹, Deanna M Santer², Daire O'Shea³, Khaled Barakat⁴, Mohammedyaseen Syedbasha⁵, Madeleine Vollmer⁵, Aliyah Baluch⁶, Rakesh Bhat², Jody Groenendyk⁷, Michael A Joyce², Luiz F Lisboa², Brad S Thomas², Manuel Battegay⁸, Nina Khanna⁸, Thomas Mueller⁹, D Lorne J Tyrrell², Michael Houghton², Atul Humar¹⁰, Deepali Kumar¹⁰

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.

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
interferon-lambda, human
Immunoglobulin G
Influenza Vaccines
Interleukins
Recombinant Proteins
Interleukin-4
Interferons

Grants and funding

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.