title: IL-28B is a key regulator of B- and T-cell vaccine responses against influenza.
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.
authors.affiliation: Infection Biology, Department of Biomedicine, University of Basel, Basel, Switzerland; Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Adrian
authors.initials: A
authors.lastname: Egli
authors.affiliation: Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Deanna M
authors.initials: DM
authors.lastname: Santer
authors.affiliation: Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada; Division of Infectious Diseases, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Daire
authors.initials: D
authors.lastname: O'Shea
authors.affiliation: Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada; Faculty of Pharmacy, University of Alberta, Canada.
authors.forename: Khaled
authors.initials: K
authors.lastname: Barakat
authors.affiliation: Infection Biology, Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Mohammedyaseen
authors.initials: M
authors.lastname: Syedbasha
authors.affiliation: Infection Biology, Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Madeleine
authors.initials: M
authors.lastname: Vollmer
authors.affiliation: Division of Infectious Diseases, Moffitt Cancer Center, Tampa, Florida, United States of America.
authors.forename: Aliyah
authors.initials: A
authors.lastname: Baluch
authors.affiliation: Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Bhat
authors.affiliation: Department of Biochemistry, School of Translational Medicine, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Jody
authors.initials: J
authors.lastname: Groenendyk
authors.affiliation: Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Joyce
authors.affiliation: Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Luiz F
authors.initials: LF
authors.lastname: Lisboa
authors.affiliation: Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Brad S
authors.initials: BS
authors.lastname: Thomas
authors.affiliation: Infection Biology, Department of Biomedicine, University of Basel, Basel, Switzerland; Division of Infectious Diseases and Hospital Epidemiology, University Hospital of Basel, Switzerland.
authors.forename: Manuel
authors.initials: M
authors.lastname: Battegay
authors.affiliation: Infection Biology, Department of Biomedicine, University of Basel, Basel, Switzerland; Division of Infectious Diseases and Hospital Epidemiology, University Hospital of Basel, Switzerland.
authors.forename: Nina
authors.initials: N
authors.lastname: Khanna
authors.affiliation: Division of Nephrology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mueller
authors.affiliation: Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: D Lorne J
authors.initials: DL
authors.lastname: Tyrrell
authors.affiliation: Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Houghton
authors.affiliation: Department of Medicine and Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada.
authors.forename: Atul
authors.initials: A
authors.lastname: Humar
authors.affiliation: Department of Medicine and Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada.
authors.forename: Deepali
authors.initials: D
authors.lastname: Kumar
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D000328:Adult; D000368:Aged; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D005260:Female; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D016867:Immunocompromised Host; D007074:Immunoglobulin G / Q000378:metabolism; D066298:In Vitro Techniques; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D007252:Influenza Vaccines / Q000276:immunology / Q000494:pharmacology*; D007251:Influenza, Human / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D007372:Interferons; D015847:Interleukin-4 / Q000378:metabolism; D007378:Interleukins / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D018417:Th1 Cells / Q000473:pathology; D018418:Th2 Cells / Q000473:pathology; D066027:Transplant Recipients; D000095022:Interferon Lambda
chemical_list: D006684:HLA-DR Antigens; D007074:Immunoglobulin G; D007252:Influenza Vaccines; D007372:Interferons; D015847:Interleukin-4; D007378:Interleukins; D011994:Recombinant Proteins; C000624353:interferon-lambda, human; D000095022:Interferon Lambda