The kinase mTOR modulates the antibody response to provide cross-protective immunity to lethal infection with influenza virus

Rachael Keating, Tomer Hertz, Marie Wehenkel, Tarsha L. Harris, Benjamin A. Edwards, Jennifer L. McClaren, Scott A. Brown, Sherri Surman, Zachary S. Wilson, Philip Bradley, Julia Hurwitz, Hongbo Chi, Peter C. Doherty, Paul G. Thomas, Maureen A. McGargill

Research output: Contribution to journalArticlepeer-review

137 Scopus citations

Abstract

Highly pathogenic avian influenza viruses pose a continuing global threat. Current vaccines will not protect against newly evolved pandemic viruses. The creation of 'universal' vaccines has been unsuccessful because the immunological mechanisms that promote heterosubtypic immunity are incompletely defined. We found here that rapamycin, an immunosuppressive drug that inhibits the kinase mTOR, promoted cross-strain protection against lethal infection with influenza virus of various subtypes when administered during immunization with influenza virus subtype H3N2. Rapamycin reduced the formation of germinal centers and inhibited class switching in B cells, which yielded a unique repertoire of antibodies that mediated heterosubtypic protection. Our data established a requirement for the mTORC1 complex in B cell class switching and demonstrated that rapamycin skewed the antibody response away from high-affinity variant epitopes and targeted more conserved elements of hemagglutinin. Our findings have implications for the design of a vaccine against influenza virus.

Original languageEnglish
Pages (from-to)1266-1276
Number of pages11
JournalNature Immunology
Volume14
Issue number12
DOIs
StatePublished - 1 Dec 2013
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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