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

Jordi Sintes (), Maurizio Gentile, Shuling Zhang, Yolanda Garcia-Carmona, Giuliana Magri, Linda Cassis, Daniel Segura-Garzón, Alessandra Ciociola, Emilie K. Grasset, Sabrina Bascones, Laura Comerma, Marc Pybus, David Lligé, Irene Puga, Cindy Gutzeit, Bing He, Wendy DuBois, Marta Crespo, Julio Pascual, Anna Mensa, Juan Ignacio Aróstegui, Manel Juan, Jordi Yagüe, Sergi Serrano, Josep Lloreta, Eric Meffre, Michael Hahne, Charlotte Cunningham-Rundles, Beverly A. Mock and Andrea Cerutti ()
Additional contact information
Jordi Sintes: Institut Hospital del Mar d’Investigacions Mèdiques (IMIM)
Maurizio Gentile: Institut Hospital del Mar d’Investigacions Mèdiques (IMIM)
Shuling Zhang: National Institutes of Health
Yolanda Garcia-Carmona: Icahn School of Medicine at Mount Sinai
Giuliana Magri: Institut Hospital del Mar d’Investigacions Mèdiques (IMIM)
Linda Cassis: Institut Hospital del Mar d’Investigacions Mèdiques (IMIM)
Daniel Segura-Garzón: Institut Hospital del Mar d’Investigacions Mèdiques (IMIM)
Alessandra Ciociola: Institut Hospital del Mar d’Investigacions Mèdiques (IMIM)
Emilie K. Grasset: Icahn School of Medicine at Mount Sinai
Sabrina Bascones: Institut Hospital del Mar d’Investigacions Mèdiques (IMIM)
Laura Comerma: Institut Hospital del Mar d’Investigacions Mèdiques (IMIM)
Marc Pybus: Institut Hospital del Mar d’Investigacions Mèdiques (IMIM)
David Lligé: Institut Hospital del Mar d’Investigacions Mèdiques (IMIM)
Irene Puga: Institut Hospital del Mar d’Investigacions Mèdiques (IMIM)
Cindy Gutzeit: Icahn School of Medicine at Mount Sinai
Bing He: Icahn School of Medicine at Mount Sinai
Wendy DuBois: National Institutes of Health
Marta Crespo: Institut Hospital del Mar d’Investigacions Mèdiques (IMIM)
Julio Pascual: Institut Hospital del Mar d’Investigacions Mèdiques (IMIM)
Anna Mensa: Hospital Clínic of Barcelona
Juan Ignacio Aróstegui: Hospital Clínic of Barcelona
Manel Juan: Hospital Clínic of Barcelona
Jordi Yagüe: Hospital Clínic of Barcelona
Sergi Serrano: Hospital del Mar
Josep Lloreta: Hospital del Mar
Eric Meffre: Yale University
Michael Hahne: Molecular Genetics Institute of Montpellier
Charlotte Cunningham-Rundles: Icahn School of Medicine at Mount Sinai
Beverly A. Mock: National Institutes of Health
Andrea Cerutti: Institut Hospital del Mar d’Investigacions Mèdiques (IMIM)

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-01602-4

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