Synthetic auxotrophy reveals metabolic regulation of plasma cell generation, affinity maturation, and cytokine receptor signaling

The efficiencies with which activated B lymphocytes proliferate and develop into antibody (Ab)- secreting plasma cells are critical determinants of adaptive humoral immunity and central to sustaining certain autoimmune diseases. Increasing evidence indicates that specific pathways in intermediary metabolism, or their substrate supply, influence lymphocyte differentiation and function. We now show that although stringent restriction of glutamine supply decreases proliferation and differentiation of B cells into plasma cells, glutaminolysis - a major means of metabolism of this amino acid - was only conditionally crucial in B cells and the Ab responses derived from them. Strikingly, Gls, the gene encoding the main glutaminase of lymphocytes, promoted anti-NP Ab responses at the primary and recall phases only when either glucose uptake into B cells or pyruvate into their mitochondria was also impaired. This synthetic auxotrophy involved support to a progressive expansion of mitochondrial respiration followed by plasma cell differentiation. Surprisingly, impairment of glutaminase and the mitochondrial pyruvate channel not only decreased the coupling of IL-21 stimulation to STAT3 induction, but also interferon stimulation of STAT1 activation. Together, our findings establish not only a powerful collaboration of metabolic pathways in promoting increased respiration and the development of Ab-secreting cells, but also a capacity of metabolism to modulate cytokine receptor signaling.