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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / immunology*
  • Cell Line
  • Cell Proliferation
  • Enzyme Activation
  • Gene Expression Profiling
  • HEK293 Cells
  • Humans
  • Immunoglobulin Class Switching / genetics
  • Immunoglobulin Class Switching / immunology
  • Immunoglobulin G / biosynthesis
  • Immunoglobulin G / immunology*
  • Lymphocyte Activation / immunology
  • Mechanistic Target of Rapamycin Complex 1 / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myeloid Differentiation Factor 88 / metabolism*
  • NF-kappa B / metabolism
  • Signal Transduction / immunology
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases / immunology*
  • Transmembrane Activator and CAML Interactor Protein / immunology*

Substances

  • Immunoglobulin G
  • MYD88 protein, human
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • TNFRSF13B protein, human
  • Transmembrane Activator and CAML Interactor Protein
  • MTOR protein, human
  • Mechanistic Target of Rapamycin Complex 1
  • TOR Serine-Threonine Kinases
  • Sirolimus