Mitochondrial respiration in B lymphocytes is essential for humoral immunity by controlling the flux of the TCA cycle, 2022, Urbanczyk et al

Highlights

• mtDNA in B cells is required for humoral immunity and plasma cell maturation
• mtDNA maintains OxPhos in LPS and antigen receptor-stimulated B cells
• OxPhos drives the TCA cycle in LPS-activated B cells
• OxPhos preserves phosphatidic acid and mTOR activity in activated B cells

Summary
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.

Open access, https://www.cell.com/cell-reports/fulltext/S2211-1247(22)00689-1