A Novel Role for the 4E-BP/eIF4E Axis in B Cell Antibody Class Switching

Abstract

Abstract During an immune response, activated B cells give rise to antibody secreting plasma cells to fight infection. B cells undergo a process known as antibody class switch recombination (CSR) to produce different classes of antibodies with varying effector functions. The mammalian target of Rapamycin (mTOR) signaling pathway is activated during this process and inhibition of mTOR suppresses both proliferation and differentiation into antibody secreting cells. mTOR is a kinase that is found in two distinct complexes, mTORC1 and mTORC2 and B cells deficient in mTOR have impaired survival, proliferation and differentiation. It has been shown that antibody class switch recombination requires B cell division, however it is unclear if there is another regulatory mechanism through mTOR that is independent of proliferation. The mTORC1 inhibitor rapamycin, at either low concentrations or when added after a B cell has committed to divide, suppresses class switching while preserving proliferation. Mechanistic investigation of the mTORC1 substrate 4E-BP, an inhibitor of eIF4E and cap-dependent translation, showed that blocking the 4E-BP/eIF4E axis can decrease antibody class switching independently of proliferation. Genetic deletion of 4E-BP1 and 4E-BP2 isoforms partially rescues from the effects of rapamycin on class switching to IgG1. These results uncover a novel role for mTORC1 and the 4E-BP/eIF4E axis in B cell antibody class switching, suggesting that cap-dependent translation regulates key steps in B cell differentiation. Further study of this pathway may provide mechanistic insight into antibody-mediated autoimmune diseases such as lupus and arthritis.