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Conditional Disruption of Raptor Reveals an Essential Role for mTORC1 in B Cell Development, Survival, and Metabolism

Terri N Iwata1, Julita A Ramírez1, Mark Tsang1

  • 1Department of Comparative Medicine, University of Washington, Seattle, WA 98195; and.

Journal of Immunology (Baltimore, Md. : 1950)
|August 14, 2016
PubMed

Insights

Mechanistic target of rapamycin (mTOR) signaling is crucial for early B cell development. Its disruption blocks B cell maturation, survival, and metabolism, impacting antibody production.

Area of Science:

  • Immunology
  • Cell Biology
  • Biochemistry

Background:

  • Mechanistic target of rapamycin (mTOR) is a key regulator of cellular processes, including growth and metabolism.
  • mTOR signaling is vital for T cell function, but its role in early B cell development remains largely unexplored.
  • mTOR coordinates nutrient availability with cellular growth, division, and differentiation.

Purpose of the Study:

  • To investigate the role of mTOR signaling in early B cell development.
  • To determine the impact of mTOR disruption on B cell survival, proliferation, and metabolism.
  • To elucidate the specific stage of B cell development affected by impaired mTOR signaling.

Main Methods:

  • Conditional disruption of the mTOR co-activator Raptor in developing mouse B cells.
  • Analysis of B cell development, survival, and proliferation in Raptor-deficient mice.
  • Assessment of cellular metabolism (oxidative phosphorylation and glycolysis) in Raptor-deficient B cells.
  • Treatment of mice with rapamycin, an mTOR inhibitor, to observe effects on B cell development.

Main Results:

  • mTOR is highly activated during pro- and pre-B cell stages.
  • Raptor deficiency in developing B cells caused a developmental block at the pre-B cell stage, leading to a lack of peripheral B cells and impaired antibody production.
  • Raptor-deficient pre-B cells showed reduced survival and proliferation, decreased oxidative phosphorylation and glycolysis, and impaired cellular metabolic capacity.
  • Rapamycin treatment recapitulated the early B cell developmental block observed in Raptor-deficient mice.

Conclusions:

  • mTOR signaling is essential for normal early B cell development, survival, and metabolic function.
  • Disruption of mTOR signaling impairs pre-B cell maturation and survival in a BclxL-independent manner.
  • These findings reveal a critical, previously uncharacterized role for mTOR in regulating B cell metabolism and development.

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