title: 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.forename: Derek D
authors.initials: DD
authors.lastname: Jones
authors.forename: Brian T
authors.initials: BT
authors.lastname: Gaudette
authors.forename: Joel R
authors.initials: JR
authors.lastname: Wilmore
authors.forename: Irene
authors.initials: I
authors.lastname: Chernova
authors.forename: Alexandra
authors.initials: A
authors.lastname: Bortnick
authors.forename: Brendan M
authors.initials: BM
authors.lastname: Weiss
authors.forename: David
authors.initials: D
authors.lastname: Allman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology; D000818:Animals; D000917:Antibody Formation / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000235:genetics / Q000276:immunology; D056724:Immunity, Humoral / Q000502:physiology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000235:genetics / Q000276:immunology; D010950:Plasma Cells / Q000276:immunology*; D000076223:Regulatory-Associated Protein of mTOR; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D046912:Multiprotein Complexes; D000076223:Regulatory-Associated Protein of mTOR; C540162:Rptor protein, mouse; C546843:mTOR protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases