title: Metabolic reprogramming is required for antibody production that is suppressed in anergic but exaggerated in chronically BAFF-exposed B cells.
abstract: B cell activation leads to proliferation and Ab production that can protect from pathogens or promote autoimmunity. Regulation of cell metabolism is essential to support the demands of lymphocyte growth and effector function and may regulate tolerance. In this study, we tested the regulation and role of glucose uptake and metabolism in the proliferation and Ab production of control, anergic, and autoimmune-prone B cells. Control B cells had a balanced increase in lactate production and oxygen consumption following activation, with proportionally increased glucose transporter Glut1 expression and mitochondrial mass upon either LPS or BCR stimulation. This contrasted with metabolic reprogramming of T cells, which had lower glycolytic flux when resting but disproportionately increased this pathway upon activation. Importantly, tolerance greatly affected B cell metabolic reprogramming. Anergic B cells remained metabolically quiescent, with only a modest increase in glycolysis and oxygen consumption with LPS stimulation. B cells chronically stimulated with elevated BAFF, however, rapidly increased glycolysis and Ab production upon stimulation. Induction of glycolysis was critical for Ab production, as glycolytic inhibition with the pyruvate dehydrogenase kinase inhibitor dichloroacetate sharply suppressed B cell proliferation and Ab secretion in vitro and in vivo. Furthermore, B cell-specific deletion of Glut1 led to reduced B cell numbers and impaired Ab production in vivo. Together, these data show that activated B cells require Glut1-dependent metabolic reprogramming to support proliferation and Ab production that is distinct from T cells and that this glycolytic reprogramming is regulated in tolerance.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710;
authors.forename: Alfredo
authors.initials: A
authors.lastname: Caro-Maldonado
authors.forename: Ruoning
authors.initials: R
authors.lastname: Wang
authors.forename: Amanda G
authors.initials: AG
authors.lastname: Nichols
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kuraoka
authors.forename: Sandra
authors.initials: S
authors.lastname: Milasta
authors.forename: Lillian D
authors.initials: LD
authors.lastname: Sun
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Gavin
authors.forename: E Dale
authors.initials: ED
authors.lastname: Abel
authors.forename: Garnett
authors.initials: G
authors.lastname: Kelsoe
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Green
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Rathmell
mesh_terms: D000818:Animals; D000917:Antibody Formation; D053264:B-Cell Activating Factor / Q000235:genetics / Q000378:metabolism*; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D017635:Clonal Anergy / Q000276:immunology*; D003999:Dichloroacetic Acid / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D006706:Homeostasis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
chemical_list: D053264:B-Cell Activating Factor; D051272:Glucose Transporter Type 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016271:Proto-Oncogene Proteins c-myc; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; C505720:Tnfsf13b protein, mouse; D003999:Dichloroacetic Acid; D017346:Protein Serine-Threonine Kinases; D005947:Glucose