Mammalian target of rapamycin complex 1 signalling is essential for germinal centre reaction

Immunology. 2017 Oct;152(2):276-286. doi: 10.1111/imm.12767. Epub 2017 Jul 10.

Abstract

The mammalian target of rapamycin (mTOR) is a serine-threonine kinase that has been shown to be essential for the differentiation and function of various immune cells. Earlier in vitro studies showed that mTOR signalling regulates B-cell biology by supporting their activation and proliferation. However, how mTOR signalling temporally regulates in vivo germinal centre B (GCB) cell development and differentiation into short-lived plasma cells, long-lived plasma cells and memory cells is still not well understood. In this study, we used a combined conditional/inducible knock-out system to investigate the temporal regulation of mTOR complex 1 (mTORC1) in the GCB cell response to acute lymphocytic choriomeningitis virus infection by deleting Raptor, a main component of mTORC1, specifically in B cells in pre- and late GC phase. Early Raptor deficiency strongly inhibited GCB cell proliferation and differentiation and plasma cell differentiation. Nevertheless, late GC Raptor deficiency caused only decreases in the size of memory B cells and long-lived plasma cells through poor maintenance of GCB cells, but it did not change their differentiation. Collectively, our data revealed that mTORC1 signalling supports GCB cell responses at both early and late GC phases during viral infection but does not regulate GCB cell differentiation into memory B cells and plasma cells at the late GC stage.

Keywords: B cell; cell differentiation; gene regulation.

MeSH terms

  • Adaptor Proteins, Signal Transducing / deficiency
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / immunology
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • B-Lymphocytes / enzymology*
  • B-Lymphocytes / immunology
  • B-Lymphocytes / transplantation
  • B-Lymphocytes / virology
  • Bone Marrow Transplantation
  • Cell Differentiation
  • Cell Proliferation
  • Disease Models, Animal
  • Genetic Predisposition to Disease
  • Germinal Center / enzymology*
  • Germinal Center / immunology
  • Germinal Center / virology
  • Host-Pathogen Interactions
  • Immunity, Humoral
  • Immunologic Memory
  • Lymphocyte Activation
  • Lymphocytic Choriomeningitis / enzymology*
  • Lymphocytic Choriomeningitis / genetics
  • Lymphocytic Choriomeningitis / immunology
  • Lymphocytic Choriomeningitis / virology
  • Lymphocytic choriomeningitis virus / immunology*
  • Lymphocytic choriomeningitis virus / pathogenicity
  • Mechanistic Target of Rapamycin Complex 1
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Multiprotein Complexes / deficiency
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / immunology
  • Multiprotein Complexes / metabolism*
  • Phenotype
  • Plasma Cells / enzymology
  • Plasma Cells / immunology
  • Plasma Cells / virology
  • Regulatory-Associated Protein of mTOR
  • Signal Transduction
  • TOR Serine-Threonine Kinases / deficiency
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / immunology
  • TOR Serine-Threonine Kinases / metabolism*
  • Time Factors
  • Transplantation Chimera

Substances

  • Adaptor Proteins, Signal Transducing
  • Multiprotein Complexes
  • Regulatory-Associated Protein of mTOR
  • Rptor protein, mouse
  • Mechanistic Target of Rapamycin Complex 1
  • TOR Serine-Threonine Kinases