1. mTOR intersects antibody-inducing signals from TACI in marginal zone B cells.
- Author
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Sintes J, Gentile M, Zhang S, Garcia-Carmona Y, Magri G, Cassis L, Segura-Garzón D, Ciociola A, Grasset EK, Bascones S, Comerma L, Pybus M, Lligé D, Puga I, Gutzeit C, He B, DuBois W, Crespo M, Pascual J, Mensa A, Aróstegui JI, Juan M, Yagüe J, Serrano S, Lloreta J, Meffre E, Hahne M, Cunningham-Rundles C, Mock BA, and Cerutti A
- Subjects
- Animals, Cell Line, Cell Proliferation, Enzyme Activation, Gene Expression Profiling, HEK293 Cells, Humans, Immunoglobulin Class Switching genetics, Immunoglobulin Class Switching immunology, Immunoglobulin G biosynthesis, Lymphocyte Activation immunology, Mice, Mice, Inbred C57BL, Mice, Knockout, NF-kappa B metabolism, Signal Transduction immunology, Sirolimus pharmacology, B-Lymphocytes immunology, Immunoglobulin G immunology, Mechanistic Target of Rapamycin Complex 1 immunology, Myeloid Differentiation Factor 88 metabolism, TOR Serine-Threonine Kinases immunology, Transmembrane Activator and CAML Interactor Protein immunology
- 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.
- Published
- 2017
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