Conditional disruption of Raptor reveals an essential role for mTORC1 in B cell development, survival, and metabolism.

Abstract

Abstract Mechanistic target of Rapamycin (mTOR) senses diverse environmental conditions including nutrient, growth factor and stress conditions, to regulate cellular growth, division, and differentiation. Studies examining the role of mTOR signaling in immune function have revealed critical roles for mTOR in regulating T-cell differentiation and function. However, there have been few studies investigating the role of mTOR in early B cell development and function. We found that mTORC1 activity is highly activated during the pro- and pre-B stages of mouse B cell development. Disruption of mTORC1 signaling in developing mouse B-cells resulted in a developmental block at the pre-B cell stage, with a corresponding lack of peripheral B-cells and loss of antigen-specific antibody production. Pre-B cell survival and proliferation were also significantly reduced in B-cells from mTORC1-signaling deficient mice. mTORC1-signaling deficiency resulted in a significant decrease in both oxidative phosphorylation and glycolysis indicating that loss of mTORC1 signaling in B cells results in altered cellular metabolism. Forced expression of a transgenic B-cell receptor on mTORC1-signaling deficient B-cells failed to rescue the developmental block. Collectively, our data reveal a previously uncharacterized role of mTORC1 signaling in early B-cell development and metabolism.