Mitochondrial respiration in B lymphocytes is essential for humoral immunity by controlling the flux of the TCA cycle

• Published in: Cell reports (Cambridge) 2022-06, Vol.39 (10), p.110912-110912, Article 110912
• Main Authors: Urbanczyk, Sophia, Baris, Olivier R, Hofmann, Jörg, Taudte, R Verena, Guegen, Naïg, Golombek, Florian, Castiglione, Kathrin, Meng, Xianyi, Bozec, Aline, Thomas, Jana, Weckwerth, Leonie, Mougiakakos, Dimitrios, Schulz, Sebastian R, Schuh, Wolfgang, Schlötzer-Schrehardt, Ursula, Steinmetz, Tobit D, Brodesser, Susanne, Wiesner, Rudolf J, Mielenz, Dirk
• Format: Article
• Language: English
• Subjects: Animals; B-Lymphocytes; Citric Acid Cycle; DNA, Mitochondrial - metabolism; Glycolysis - genetics; Immunity, Humoral; Life Sciences; Lipopolysaccharides - metabolism; Mice; Respiration
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.110912

To elucidate the function of oxidative phosphorylation (OxPhos) during B cell differentiation, we employ CD23Cre-driven expression of the dominant-negative K320E mutant of the mitochondrial helicase Twinkle (DNT). DNT-expression depletes mitochondrial DNA during B cell maturation, reduces the abundance of respiratory chain protein subunits encoded by mitochondrial DNA, and, consequently, respiratory chain super-complexes in activated B cells. Whereas B cell development in DNT mice is normal, B cell proliferation, germinal centers, class switch to IgG, plasma cell maturation, and T cell-dependent as well as T cell-independent humoral immunity are diminished. DNT expression dampens OxPhos but increases glycolysis in lipopolysaccharide and B cell receptor-activated cells. Lipopolysaccharide-activated DNT-B cells exhibit altered metabolites of glycolysis, the pentose phosphate pathway, and the tricarboxylic acid cycle and a lower amount of phosphatidic acid. Consequently, mTORC1 activity and BLIMP1 induction are curtailed, whereas HIF1α is stabilized. Hence, mitochondrial DNA controls the metabolism of activated B cells via OxPhos to foster humoral immunity.