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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.
Highlights
Mechanistic target of rapamycin enhances immunity in addition to orchestrating metabolism
Besides activating X box protein-1 (XBP-1)-regulated unfolded protein response (UPR) programs required for antibody synthesis and secretion[12], B-lymphocyte-induced maturation protein-1 (BLIMP-1) transcriptionally suppresses paired-box containing-5 (PAX5)-orchestrated B-cell identity programs involved in B-cell proliferation, class switch recombination (CSR) and SHM13
We show that elevated transmembrane activator and CAML interactor (TACI) expression correlated with increased Mechanistic target of rapamycin (mTOR) activation in pre-activated marginal zone (MZ) B cells
Summary
Mechanistic target of rapamycin (mTOR) enhances immunity in addition to orchestrating metabolism. 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). Unlike follicular B cells, which follow a T-cell-dependent pathway requiring CD40 ligand (CD40L), MZ B cells follow a T-cell-independent pathway involving B-cellactivating factor of the tumor necrosis family (BAFF) and a proliferation-inducing ligand (APRIL)[1,2] These CD40L-related cytokines derive from innate immune cells and activate MZ B cells via transmembrane activator and CAML interactor (TACI)[3,4,5,6], a receptor that induces antibody production in concert with B-cell antigen receptor (BCR) and Toll-like receptors (TLR)[7]. Aside from lipid and nucleic acid synthesis, mTORC1 enhances protein synthesis by suppressing inhibitors of eukaryotic translation initiation factor 4E (eIF4E) and activating ribosomal S6 inducers of protein translation16. mTORC1 coordinates these anabolic processes with nutrient intake, glycolysis, and mitochondrial respiration, as well as mitochondrial, endoplasmic reticulum (ER), ribosome, and lysosome biogenesis, through various transcription factors, including sterol regulatory element-binding proteins (SREBP), peroxisome proliferator-activated receptor-γ (PPARγ), hypoxia-inducible factor 1α (HIF1α) and MYC14,16
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