Metabolic Reprogramming is Required for Antibody Production That is Suppressed in Anergic but Exaggerated in Chronically BAFF-Exposed B cells
| Autor: | Douglas R. Green, Lillian D. Sun, Masayuki Kuraoka, Garnett Kelsoe, Alfredo Caro-Maldonado, E. Dale Abel, Amanda G. Nichols, Amanda L. Gavin, Jeffrey C. Rathmell, Sandra Milasta, Ruoning Wang |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Pyruvate dehydrogenase kinase
Lymphocyte T-Lymphocytes Immunology Mice Transgenic Biology Mitochondrion Protein Serine-Threonine Kinases Lymphocyte Activation Article Proto-Oncogene Proteins c-myc Mice B-Cell Activating Factor medicine Immunology and Allergy Animals Homeostasis Humans Glycolysis B cell Clonal Anergy B-Lymphocytes Glucose Transporter Type 1 Clonal anergy Dichloroacetic Acid Glucose transporter Pyruvate Dehydrogenase Acetyl-Transferring Kinase Hypoxia-Inducible Factor 1 alpha Subunit Cell biology Mitochondria medicine.anatomical_structure Glucose Biochemistry Antibody Formation Reprogramming |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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