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mTOR kinase inhibitors promote antibody class switching via mTORC2 inhibition

Jose J Limon1, Lomon So1, Stefan Jellbauer2

  • 1Department of Molecular Biology & Biochemistry, Institute for Immunology, and.

Proceedings of the National Academy of Sciences of the United States of America
|November 12, 2014
PubMed

Insights

ATP-competitive mTOR kinase inhibitors (TOR-KIs) enhance B-cell class switching and antibody production, unlike rapamycin. These findings suggest TOR-KIs could improve vaccine responses by boosting antibody generation.

Area of Science:

  • Immunology
  • Cell Biology
  • Pharmacology

Background:

  • Mammalian target of rapamycin (mTOR) signaling is crucial for B-cell function, operating through mTORC1 and mTORC2 complexes.
  • Rapamycin, an mTORC1 inhibitor, differentially affects B-cell responses, with low doses promoting IgM production.
  • The impact of ATP-competitive mTOR kinase inhibitors (TOR-KIs), which inhibit both mTORC1 and mTORC2, on mature lymphocytes remains largely unexplored.

Purpose of the Study:

  • To investigate the complex roles of mTOR signaling in B-cell differentiation and antibody class switching.
  • To compare the effects of TOR-KIs with rapamycin on B-cell responses.
  • To explore the potential of TOR-KIs for enhancing antibody production, particularly in the context of vaccination.

Main Methods:

  • Utilized ATP-competitive mTOR kinase inhibitors (TOR-KIs) to study B-cell responses in vitro and in vivo.
  • Assessed B-cell proliferation, differentiation, and class switching under varying TOR-KI concentrations.
  • Administered TOR-KI compound AZD8055 to mice to evaluate its effect on antibody titers.
  • Investigated the mechanistic basis of TOR-KI-mediated enhancement of class switching, focusing on forkhead box, subgroup O (FoxO) transcription factors.

Main Results:

  • High TOR-KI concentrations suppressed B-cell proliferation and differentiation, while lower concentrations enhanced B-cell class switching in vitro.
  • Transient in vivo treatment with AZD8055 increased titers of class-switched, high-affinity antibodies.
  • mTORC1 and mTORC2 exhibit opposing roles in B-cell differentiation.
  • TOR-KIs enhance B-cell class switching in a FoxO-dependent manner.

Conclusions:

  • TOR-KIs exhibit distinct effects compared to rapamycin, offering a different approach to modulating B-cell responses.
  • Lower doses of TOR-KIs can promote B-cell class switching and high-affinity antibody production.
  • TOR-KIs represent a potential therapeutic strategy to augment antibody responses, particularly for enhancing vaccine efficacy.
Keywords:
B lymphocyteclass switchingdifferentiationkinaserapamycin

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