mTOR has distinct functions in generating versus sustaining humoral immunity
Derek D. Jones, … , Brendan M. Weiss, David Allman
Derek D. Jones, … , Brendan M. Weiss, David Allman
Published October 17, 2016
Citation Information: J Clin Invest. 2016;126(11):4250-4261. https://doi.org/10.1172/JCI86504.
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Research Article Immunology

mTOR has distinct functions in generating versus sustaining humoral immunity

Abstract

Little is known about the role of mTOR signaling in plasma cell differentiation and function. Furthermore, for reasons not understood, mTOR inhibition reverses antibody-associated disease in a murine model of systemic lupus erythematosus. Here, we have demonstrated that induced B lineage–specific deletion of the gene encoding RAPTOR, an essential signaling adaptor for rapamycin-sensitive mTOR complex 1 (mTORC1), abrogated the generation of antibody-secreting plasma cells in mice. Acute treatment with rapamycin recapitulated the effects of RAPTOR deficiency, and both strategies led to the ablation of newly formed plasma cells in the spleen and bone marrow while also obliterating preexisting germinal centers. Surprisingly, although perturbing mTOR activity caused a profound decline in serum antibodies that were specific for exogenous antigen or DNA, frequencies of long-lived bone marrow plasma cells were unaffected. Instead, mTORC1 inhibition led to decreased expression of immunoglobulin-binding protein (BiP) and other factors needed for robust protein synthesis. Consequently, blockade of antibody synthesis was rapidly reversed after termination of rapamycin treatment. We conclude that mTOR signaling plays critical but diverse roles in early and late phases of antibody responses and plasma cell differentiation.

Authors

Derek D. Jones, Brian T. Gaudette, Joel R. Wilmore, Irene Chernova, Alexandra Bortnick, Brendan M. Weiss, David Allman

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Figure 5

mTOR signaling regulates genes required for efficient protein translation in plasma cells.

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mTOR signaling regulates genes required for efficient protein translatio...
B6.BLIMP1+/GFP mice were treated with rapamycin 7 times over 16 days, and B220− BM plasma cells were sorted for microarray analysis. (A) Volcano plot comparing the fold change (log2) versus P values associated with gene expression in BM plasma cells. Genes that exceeded a 1.5-fold change are highlighted in red. (B) Heat map comparing differentially expressed genes in BM plasma cells from control and rapamycin-treated mice. Each column represents the gene expression profile for B220− plasma cells sorted from a single mouse; data indicate the row Z score. (C) Control or rapamycin-treated B220− BM plasma cells were sorted from 3–4 individual B6.BLIMP1+/GFP mice for cDNA synthesis, and levels for the indicated genes were quantified using qRT-PCR with Taqman probes. Symbols indicate results for individual mice, red lines indicate mean 2–ΔCt values, and error bars indicate standard deviations. Indicated P values were determined by Student’s t test comparing control and treated mice. n.d., not detected.