mTOR kinase inhibitors promote antibody class switching via mTORC2 inhibition.
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.
Department of Molecular Biology & Biochemistry, Institute for Immunology, and.
Jose J
JJ
Limon
Department of Molecular Biology & Biochemistry, Institute for Immunology, and.
Lomon
L
So
Institute for Immunology, and Department of Microbiology & Molecular Genetics, University of California, Irvine, CA 92697; and.
Stefan
S
Jellbauer
Department of Molecular Biology & Biochemistry, Institute for Immunology, and.
Honyin
H
Chiu
Department of Molecular Biology & Biochemistry.
Juana
J
Corado
Fox Chase Cancer Center, Philadelphia, PA 19111.
Stephen M
SM
Sykes
Institute for Immunology, and Department of Microbiology & Molecular Genetics, University of California, Irvine, CA 92697; and.
Manuela
M
Raffatellu
Department of Molecular Biology & Biochemistry, Institute for Immunology, and dfruman@uci.edu.
David A
DA
Fruman
D000494:Allosteric Regulation; D000818:Animals; D017578:Immunoglobulin Class Switching / Q000187:drug effects*; D007074:Immunoglobulin G / Q000096:biosynthesis; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
D007074:Immunoglobulin G; D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
B lymphocyte; class switching; differentiation; kinase; rapamycin