MTOR kinase inhibitors promote antibody class switching via mTORC2 inhibition

Jose J. Limon, Lomon So, Stefan Jellbauer, Honyin Chiu, Juana Corado, Stephen M. Sykes, Manuela Raffatellu, David A. Fruman

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

Abstract

The mammalian target of rapamycin (mTOR) is a kinase that functions in two distinct complexes, mTORC1 and mTORC2. In peripheral B cells, complete deletion of mTOR suppresses germinal center B-cell responses, including class switching and somatic hypermutation. The allosteric mTORC1 inhibitor rapamycin blocks proliferation and differentiation, but lower doses can promote protective IgM responses. To elucidate the complexity of mTOR signaling in B cells further, we used ATP-competitive mTOR kinase inhibitors (TOR-KIs), which inhibit both mTORC1 and mTORC2. Although TOR-KIs are in clinical development for cancer, their effects on mature lymphocytes are largely unknown. We show that high concentrations of TOR-KIs suppress B-cell proliferation and differentiation, yet lower concentrations that preserve proliferation increase the fraction of B cells undergoing class switching in vitro. Transient treatment of mice with the TOR-KI compound AZD8055 increased titers of class-switched high-affinity antibodies to a hapten-protein conjugate. Mechanistic investigation identified opposing roles for mTORC1 and mTORC2 in B-cell differentiation and showed that TOR-KIs enhance class switching in a manner dependent on forkhead box, subgroup O (FoxO) transcription factors. These observations emphasize the distinct actions of TOR-KIs compared with rapamycin and suggest that TOR-KIs might be useful to enhance production of class-switched antibodies following vaccination.

Original languageEnglish
Pages (from-to)E5076-E5085
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number47
DOIs
StatePublished - Nov 25 2014

Keywords

  • Blymphocyte
  • Class switching
  • Differentiation
  • Kinase
  • Rapamycin

Fingerprint

Dive into the research topics of 'MTOR kinase inhibitors promote antibody class switching via mTORC2 inhibition'. Together they form a unique fingerprint.

Cite this