B Cell-Intrinsic mTORC1 Promotes Germinal Center-Defining Transcription Factor Gene Expression, Somatic Hypermutation, and Memory B Cell Generation in Humoral Immunity.

Raybuck AL, Cho SH, Li J, Rogers MC, Lee K, Williams CL, Shlomchik M, Thomas JW, Chen J, Williams JV, Boothby MR
J Immunol. 2018 200 (8): 2627-2639

PMID: 29531165 · PMCID: PMC5893413 · DOI:10.4049/jimmunol.1701321

B lymphocytes migrate among varied microenvironmental niches during diversification, selection, and conversion to memory or Ab-secreting plasma cells. Aspects of the nutrient milieu differ within these lymphoid microenvironments and can influence signaling molecules such as the mechanistic target of rapamycin (mTOR). However, much remains to be elucidated as to the B cell-intrinsic functions of nutrient-sensing signal transducers that modulate B cell differentiation or Ab affinity. We now show that the amino acid-sensing mTOR complex 1 (mTORC1) is vital for induction of Bcl6-a key transcriptional regulator of the germinal center (GC) fate-in activated B lymphocytes. Accordingly, disruption of mTORC1 after B cell development and activation led to reduced populations of Ag-specific memory B cells as well as plasma cells and GC B cells. In addition, induction of the germ line transcript that guides activation-induced deaminase in selection of the IgG1 H chain region during class switching required mTORC1. Expression of the somatic mutator activation-induced deaminase was reduced by a lack of mTORC1 in B cells, whereas point mutation frequencies in Ag-specific GC-phenotype B cells were only halved. These effects culminated in a B cell-intrinsic defect that impacted an antiviral Ab response and drastically impaired generation of high-affinity IgG1. Collectively, these data establish that mTORC1 governs critical B cell-intrinsic mechanisms essential for establishment of GC differentiation and effective Ab production.

Copyright © 2018 by The American Association of Immunologists, Inc.

MeSH Terms (17)

Animals B-Lymphocytes Cell Differentiation Gene Expression Germinal Center Immunity, Humoral Immunoglobulin G Immunologic Memory Lymphocyte Activation Mechanistic Target of Rapamycin Complex 1 Mice Mice, Inbred C57BL Mutation Plasma Cells Proto-Oncogene Proteins c-bcl-6 Signal Transduction Transcription Factors

Connections (3)

This publication is referenced by other Labnodes entities:

Links