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

Nat Immunol. 2013 Dec;14(12):1266-76. doi: 10.1038/ni.2741. Epub 2013 Oct 20.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity / immunology*
  • Animals
  • Antibodies, Viral / immunology
  • Antibody Formation / immunology*
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • Cell Line
  • Female
  • Flow Cytometry
  • Host-Pathogen Interactions / immunology
  • Immunoglobulin Class Switching / drug effects
  • Immunoglobulin Class Switching / immunology
  • Immunoglobulin M / immunology
  • Immunosuppressive Agents / pharmacology
  • Influenza A Virus, H3N2 Subtype / immunology
  • Influenza A Virus, H3N2 Subtype / physiology
  • Influenza A Virus, H5N1 Subtype / immunology
  • Influenza A Virus, H5N1 Subtype / physiology
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Multiprotein Complexes / immunology
  • Multiprotein Complexes / metabolism
  • Orthomyxoviridae / classification
  • Orthomyxoviridae / immunology*
  • Orthomyxoviridae / physiology
  • Orthomyxoviridae Infections / immunology*
  • Orthomyxoviridae Infections / prevention & control
  • Orthomyxoviridae Infections / virology
  • Sirolimus / pharmacology
  • Survival Analysis
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / immunology*
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Antibodies, Viral
  • Immunoglobulin M
  • Immunosuppressive Agents
  • Multiprotein Complexes
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Mechanistic Target of Rapamycin Complex 1
  • Sirolimus