Mitochondrial function is essential for humoral immunity by controlling flux of the TCA cycle, phosphatidic acid and mTOR activity in B cells

The function of mitochondrial respiration during B cell fate decisions and differentiation remains equivocal. This study reveals that selection for mitochondrial fitness occurs during B cell activation and is essential for subsequent plasma cell differentiation. By expressing a mutated mitochondrial helicase in transitional B cells, we depleted mitochondrial DNA during B cell maturation, resulting in reduced oxidative phosphorylation. Although no changes in follicular B cell development were evident, germinal centers, class switch recombination to IgG, plasma cell generation and humoral immunity were diminished. Defective oxidative phosphorylation led to aberrant flux of the tricarboxylic acid cycle and lowered the amount of saturated phosphatidic acid. Consequently, MTOR activity and BLIMP-1 induction were curtailed whereas HIF1α, glycolysis and AMPK activity were amplified. Exogenous phosphatidic acid increased mTOR activity in activated B cells. Hence, mitochondrial function is required and selected for in activated B cells for the successful generation of functional plasma cells. * Abbreviations : Ab : antibody AMPK : Adenosine monophosphate activated kinase BCR : B cell receptor BM : bone marrow CSR : class switch recombination ETC : electron transport chain FA : fatty acid FAD : flavine adenine dinucleotide GC : germinal center G3P : Glyceraldehyde-3-phosphate GPL : glycerophospholipid IMM : inner mitochondrial membrane IRF4 : Interferon regulatory factor 4 LC-MS : liquid chromatography mass spectrometry LPA : lysophosphatidic acid LPAAT : Lysophosphatidic acid acyltransferase MZ : marginal zone mtDNA : mitochondrial DNA mtRC : mitochondrial respiratory chain NAD : nicotinamide adenine dinucleotide NP-KLH : Nitrophenol keyhole limpet hemocyanin PEP : phosphoenolpyruvate PA : phosphatidic acid PC : phosphatidylcholine PE : phosphatidylethanolamine PG : phosphatidylglycerol PI : phosphoinositol PS : phoshphatidylserine PI3K : phosphoinositol-3-kinase pRPS6 : phosphorylated ribosomal protein RPS6 SRBC : sheep red blood cell SHM : somatic hypermutation SDH : Succinatedehydrogenase TCA : tricarboxylic acid cycle TD : T-cell dependent TI : T-cell independent UDPNAG : Uridine Diphosphate N-acetylglucosamine vHL : von Hippel-Lindau protein