Initial B Cell Activation Induces Metabolic Reprogramming and Mitochondrial Remodeling
Lynnea R. Waters,
Fasih M. Ahsan,
Dane M. Wolf,
Orian Shirihai,
Michael A. Teitell
Affiliations
Lynnea R. Waters
Molecular Biology Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
Fasih M. Ahsan
Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
Dane M. Wolf
Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Division of Endocrinology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA
Orian Shirihai
Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Division of Endocrinology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA
Michael A. Teitell
Molecular Biology Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Pediatrics, Department of Bioengineering, Broad Stem Cell Research Center, Jonsson Comprehensive Cancer Center, and California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Corresponding author
Summary: B lymphocytes provide adaptive immunity by generating antigen-specific antibodies and supporting the activation of T cells. Little is known about how global metabolism supports naive B cell activation to enable an effective immune response. By coupling RNA sequencing (RNA-seq) data with glucose isotopomer tracing, we show that stimulated B cells increase programs for oxidative phosphorylation (OXPHOS), the tricarboxylic acid (TCA) cycle, and nucleotide biosynthesis, but not glycolysis. Isotopomer tracing uncovered increases in TCA cycle intermediates with almost no contribution from glucose. Instead, glucose mainly supported the biosynthesis of ribonucleotides. Glucose restriction did not affect B cell functions, yet the inhibition of OXPHOS or glutamine restriction markedly impaired B cell growth and differentiation. Increased OXPHOS prompted studies of mitochondrial dynamics, which revealed extensive mitochondria remodeling during activation. Our results show how B cell metabolism adapts with stimulation and reveals unexpected details for carbon utilization and mitochondrial dynamics at the start of a humoral immune response. : Immunology; Immune Response; Components of the Immune System; Metabolomics Subject Areas: Immunology, Immune Response, Components of the Immune System, Metabolomics
