IL-28B is a Key Regulator of B- and T-Cell Vaccine Responses against Influenza

PLoS Pathogens

Brad S. Thomas¹  Michael Houghton²  Deepali Kumar²  Michael A. Joyce³  Mohammedyaseen Syedbasha⁴  Aliyah Baluch⁵  Atul Humar⁶  D. Lorne J. Tyrrell⁶  Adrian Egli⁶  Rakesh Bhat⁶  Jody Groenendyk⁶  Daire O'Shea⁷  Madeleine Vollmer⁷  Thomas Mueller⁷  Manuel Battegay⁷  Deanna M. Santer⁷  Luiz F. Lisboa⁷  Khaled Barakat⁷  Nina Khanna⁷ 

[1] Department of Biochemistry, School of Translational Medicine, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada;Division of Infectious Diseases and Hospital Epidemiology, University Hospital of Basel, Switzerland;Division of Infectious Diseases, Moffitt Cancer Center, Tampa, Florida, United States of America;Division of Infectious Diseases, University of Alberta, Edmonton, Alberta, Canada;Faculty of Pharmacy, University of Alberta, Canada;Infection Biology, Department of Biomedicine, University of Basel, Basel, Switzerland;Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada

关键词: Cytokines;    Influenza;    B cells;    Vaccines;    H1N1;    Vaccination;    immunization;    T cells;    Immune response;   

DOI  :  10.1371/journal.ppat.1004556

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY