A dangeROS liaison: the metabolism-dependent regulation of B lymphocytes. (Doctoral thesis)
- Experimental and Molecular Immunology
Marginal and follicular B cells (MZB and FoB) possess diverse developmental, phenotypic, functional and transcriptomic attributes at steady state. The engagement of distinct redox systems contributes to the metabolic reprogramming of immune cells. However, the function of the main intracellular antioxidant glutathione (GSH) in the context of B cells redoxtasis is unknown. By using mice with B cell-specific ablation of the catalytic subunit of glutamate cysteine ligase (Gclc), we show that GSH loss affects the homeostatic persistence of MZB and that GSH-dependent redox regulation is critical for the control of MZB versus FoB metabolic dependencies. Although Gclc ablation does not prevent the formation of FoB, Gclc-depleted mice exhibit ineffective germinal center reactions and null antibody response upon in vivo viral infection. Similarly to wild-type MZB, Gclc-deficient FoB show increased ATP levels, glucose metabolism, mTOR activation, and protein synthesis but accumulate defective mitochondria. Moreover, blocking of glucose uptake in vitro limits ATP production and accelerates apoptosis in Gclc-deficient FoB. Thus, GSH-dependent redox control is crucial for B cell activation and determines the metabolic identity of MZB and FoB.