title: The kinase mTOR modulates the antibody response to provide cross-protective immunity to lethal infection with influenza virus.
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.
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Rachael
authors.initials: R
authors.lastname: Keating
authors.forename: Tomer
authors.initials: T
authors.lastname: Hertz
authors.forename: Marie
authors.initials: M
authors.lastname: Wehenkel
authors.forename: Tarsha L
authors.initials: TL
authors.lastname: Harris
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Edwards
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: McClaren
authors.forename: Scott A
authors.initials: SA
authors.lastname: Brown
authors.forename: Sherri
authors.initials: S
authors.lastname: Surman
authors.forename: Zachary S
authors.initials: ZS
authors.lastname: Wilson
authors.forename: Philip
authors.initials: P
authors.lastname: Bradley
authors.forename: Julia
authors.initials: J
authors.lastname: Hurwitz
authors.forename: Hongbo
authors.initials: H
authors.lastname: Chi
authors.forename: Peter C
authors.initials: PC
authors.lastname: Doherty
authors.forename: Paul G
authors.initials: PG
authors.lastname: Thomas
authors.forename: Maureen A
authors.initials: MA
authors.lastname: McGargill
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology*; D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D000917:Antibody Formation / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D005260:Female; D005434:Flow Cytometry; D054884:Host-Pathogen Interactions / Q000276:immunology; D017578:Immunoglobulin Class Switching / Q000187:drug effects / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D053122:Influenza A Virus, H3N2 Subtype / Q000276:immunology / Q000502:physiology; D053124:Influenza A Virus, H5N1 Subtype / Q000276:immunology / Q000502:physiology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000276:immunology / Q000378:metabolism; D009975:Orthomyxoviridae / Q000145:classification / Q000276:immunology* / Q000502:physiology; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000517:prevention & control / Q000821:virology; D020123:Sirolimus / Q000494:pharmacology; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism
chemical_list: D000914:Antibodies, Viral; D007075:Immunoglobulin M; D007166:Immunosuppressive Agents; D046912:Multiprotein Complexes; C546843:mTOR protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus