mTOR intersects antibody-inducing signals from TACI in marginal zone B cells

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  • dc.contributor.author Sintes, Jordica
  • dc.contributor.author Serrano Figueras, Sergica
  • dc.contributor.author Lloreta, Josep, 1958-ca
  • dc.contributor.author Cerutti, Andrea, 1965-ca
  • dc.date.accessioned 2018-03-19T14:33:53Z
  • dc.date.available 2018-03-19T14:33:53Z
  • dc.date.issued 2017
  • dc.description.abstract Mechanistic target of rapamycin (mTOR) enhances immunity in addition to orchestrating metabolism. Here we show that mTOR coordinates immunometabolic reconfiguration of marginal zone (MZ) B cells, a pre-activated lymphocyte subset that mounts antibody responses to T-cell-independent antigens through a Toll-like receptor (TLR)-amplified pathway involving transmembrane activator and CAML interactor (TACI). This receptor interacts with mTOR via the TLR adapter MyD88. The resulting mTOR activation instigates MZ B-cell proliferation, immunoglobulin G (IgG) class switching, and plasmablast differentiation through a rapamycin-sensitive pathway that integrates metabolic and antibody-inducing transcription programs, including NF-κB. Disruption of TACI-mTOR interaction by rapamycin, truncation of the MyD88-binding domain of TACI, or B-cell-conditional mTOR deficiency interrupts TACI signaling via NF-κB and cooperation with TLRs, thereby hampering IgG production to T-cell-independent antigens but not B-cell survival. Thus, mTOR drives innate-like antibody responses by linking proximal TACI signaling events with distal immunometabolic transcription programs.
  • dc.description.sponsorship T.T. was supported by the Academy of Finland (285725), Finnish Cultural Foundation, Orion-Farmos Research Foundation and Emil Aaltonen Foundation. K.J.K. is supported by a NIGMS Fellowship (F32GM115208). This work was supported by NIH grants U54DK105566, R01MH101820 and R01GM104371 to D.G.M. The Genotype-Tissue Expression (GTEx) project was supported by the Common Fund of the Office of the Director of the National Institutes of Health. Additional funds were provided by the NCI, NHGRI, NHLBI, NIDA, NIMH and NINDS. Donors were enrolled at Biospecimen Source Sites funded by NCI\SAIC-Frederick, Inc. (SAIC-F) subcontracts to the National Disease Research Interchange (10XS170), Roswell Park Cancer Institute (10XS171) and Science Care, Inc. (X10S172). The Laboratory, Data Analysis, and Coordinating Center (LDACC) was funded through a contract (HHSN268201000029C) to The Broad Institute; this grant also provided funding to D.G.M. and T.T. Biorepository operations were funded through an SAIC-F subcontract to the Van Andel Institute (10ST1035). Additional data repository and project management were provided by SAIC-F (HHSN261200800001E). The Brain Bank was supported by supplements to University of Miami grants DA006227 and DA033684 and to contract N01MH000028. Statistical Methods development grants were made to the University of Geneva (MH090941 and MH101814), the University of Chicago (MH090951, MH090937, MH101820 and MH101825), the University of North Carolina, Chapel Hill (MH090936 and MH101819), Harvard University (MH090948), Stanford University (MH101782), Washington University St. Louis (MH101810) and the University of Pennsylvania (MH101822).
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Sintes J, Gentile M, Zhang S, Garcia-Carmona Y, Magri G, Cassis L et al. mTOR intersects antibody-inducing signals from TACI in marginal zone B cells. Nat Commun. 2017 Nov 13;8(1):1462. DOI: 10.1038/s41467-017-01602-4
  • dc.identifier.doi http://dx.doi.org/10.1038/s41467-017-01602-4
  • dc.identifier.issn 2041-1723
  • dc.identifier.uri http://hdl.handle.net/10230/34205
  • dc.language.iso eng
  • dc.publisher Nature Publishing Groupca
  • dc.relation.ispartof Nature Communications. 2017 Nov 13;8(1):1462
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/SAF2011-25241
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2014-52483-R
  • dc.rights © Nature Publishing Group. http://dx.doi.org/10.1038/s41467-017-01602-4 Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.keyword Class switch recombination
  • dc.subject.keyword Marginal zone B cells
  • dc.title mTOR intersects antibody-inducing signals from TACI in marginal zone B cellsca
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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