The mTORC1/4E-BP/eIF4E axis promotes antibody class switching in B lymphocytes

Honyin Chiu, Leandra V. Jackson, Kwon Ik Oh, Annie Mai, Ze'ev A. Ronai, Davide Ruggero, David A. Fruman

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

During an adaptive immune response, activated mature B cells give rise to Ab-secreting plasma cells to fight infection. B cells undergo Ab class switching to produce different classes of Abs with varying effector functions. The mammalian/mechanistic target of rapamycin (mTOR) signaling pathway is activated during this process, and disrupting mTOR complex 1 (mTORC1) in B cells impairs class switching by a poorly understood mechanism. In particular, it is unclear which mTORC1 downstream substrates control this process. In this study, we used an in vitro murine model in which the mTORC1 inhibitor rapamycin, when added after a B cell has committed to divide, suppresses class switching while preserving proliferation. Investigation of mTORC1 substrates revealed a role for eukaryotic translation initiation factor 4E (eIF4E) and eIF4E-binding proteins in class switching. Mechanistically, we show that genetic or pharmacological disruption of eIF4E binding to eIF4G reduced cap-dependent translation, which specifically affected the expression of activation-induced cytidine deaminase protein but not Aicda mRNA. This translational impairment decreased Ab class switching independently of proliferation. These results uncover a previously undescribed role for mTORC1 and the eIF4E-binding proteins/ eIF4E axis in activation-induced cytidine deaminase protein expression and Ab class switching in mouse B cells, suggesting that cap-dependent translation regulates key steps in B cell differentiation.

Original languageEnglish
Pages (from-to)579-590
Number of pages12
JournalJournal of Immunology
Volume202
Issue number2
DOIs
StatePublished - 15 Jan 2019
Externally publishedYes

Fingerprint

Dive into the research topics of 'The mTORC1/4E-BP/eIF4E axis promotes antibody class switching in B lymphocytes'. Together they form a unique fingerprint.

Cite this