Journal article
Metabolic Reprogramming is Required for Antibody Production That is Suppressed in Anergic but Exaggerated in Chronically BAFF-Exposed B cells
The Journal of immunology (1950), Vol.192(8), pp.3626-3636
04/15/2014
DOI: 10.4049/jimmunol.1302062
PMCID: PMC3984038
PMID: 24616478
Abstract
B cell activation leads to proliferation and antibody 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. Here, we tested the regulation and role of glucose uptake and metabolism in the proliferation and antibody 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 B cell Activating Factor (BAFF), however, rapidly increased glycolysis and antibody production upon stimulation. Induction of glycolysis was critical for antibody production, as glycolytic inhibition with the pyruvate dehydrogenase kinase (PDHK) inhibitor dichloroacetate (DCA) sharply suppressed B cell proliferation and antibody secretion
in vitro
and
in vivo
. Further, B cell-specific deletion of Glut1 led to reduced B cell numbers and impaired antibody production
in vivo
. Together, these data show that activated B cells require Glut1-dependent metabolic reprogramming to support proliferation and antibody production that is distinct from T cells and that this glycolytic reprogramming is regulated in tolerance.
Details
- Title: Subtitle
- Metabolic Reprogramming is Required for Antibody Production That is Suppressed in Anergic but Exaggerated in Chronically BAFF-Exposed B cells
- Creators
- Alfredo Caro-Maldonado - Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USARuoning Wang - Center for Childhood Cancer and Blood Disease, The Research Institute at Nationwide Children’s Hospital, The Ohio State University School of Medicine, Columbus, OH 43205, USAAmanda G Nichols - Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USAMasayuki Kuraoka - Department of Immunology, Duke University, Durham, NC 27710, USASandra Milasta - Department of Immunology, St. Jude Children’s Research Hospital, IRC-E7050, MS 351, 262 Danny Thomas Place, Memphis, TN 38105, USALillian D Sun - Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USAAmanda L Gavin - Center for Immunology, Burnet Institute, 85 Commercial Rd, Melbourne VIC 3004, AustraliaE. Dale Abel - Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Department of Medicine, Carver College of Medicine University of Iowa, Iowa City, IA 52242, USAGarnett Kelsoe - Department of Immunology, Duke University, Durham, NC 27710, USADouglas R Green - Department of Immunology, St. Jude Children’s Research Hospital, IRC-E7050, MS 351, 262 Danny Thomas Place, Memphis, TN 38105, USAJeffrey C Rathmell - Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA
- Resource Type
- Journal article
- Publication Details
- The Journal of immunology (1950), Vol.192(8), pp.3626-3636
- DOI
- 10.4049/jimmunol.1302062
- PMID
- 24616478
- PMCID
- PMC3984038
- NLM abbreviation
- J Immunol
- ISSN
- 0022-1767
- eISSN
- 1550-6606
- Language
- English
- Date published
- 04/15/2014
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984024540702771
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