Direct activation of mTOR in B lymphocytes confers impairment in B-cell maturation andloss of marginal zone B cells

Eur J Immunol. 2011 Aug;41(8):2390-6. doi: 10.1002/eji.201041336. Epub 2011 Jun 24.

Abstract

The tuberous sclerosis complex (TSC), composed of TSC1/TSC2 heterodimers, is inhibitory to the mammalian target of rapamycin (mTOR). Deletion of either TSC1 or TSC2 renders mTOR constitutively active. To directly explore the impact of mTOR activation on B-cell development, we conditionally deleted TSC1 in murine B cells. This led to impairment in B-cell maturation. Unexpectedly, and in contrast to Akt activation, marginal zone (MZ) B cells were significantly reduced. Administration of rapamycin partially corrected the MZ defect, indicating a direct role for mTOR in controlling MZ development. When challenged with a T-cell-dependent antigen, TSC1 KO mice responded less efficiently. Consistent with the MZ defects, TSC1 KO mice did not respond at all to T-independent antigens. Because activation of Akt upstream of TSC and mTOR yields the reverse phenotype with respect to MZ development, we conclude that, physiologically, Akt simultaneously emits two opposing signals that counterbalance each other in the control of B-cell differentiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / cytology
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / metabolism*
  • Cell Differentiation / genetics
  • Cells, Cultured
  • Female
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Germinal Center / metabolism
  • Immunization
  • Immunosuppressive Agents / pharmacology
  • Male
  • Mice
  • Mice, Knockout
  • Polymerase Chain Reaction
  • Proto-Oncogene Proteins c-akt / metabolism
  • Sirolimus / pharmacology
  • Spleen / cytology
  • Spleen / metabolism
  • TOR Serine-Threonine Kinases / metabolism*
  • Tuberous Sclerosis Complex 1 Protein
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism

Substances

  • Immunosuppressive Agents
  • Tsc1 protein, mouse
  • Tsc2 protein, mouse
  • Tuberous Sclerosis Complex 1 Protein
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Proto-Oncogene Proteins c-akt
  • Sirolimus