Mogilenko, D. | bioRxiv Science

bioRxiv2025

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 sustain certain autoimmune diseases. 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 if either glucose uptake into B cells or pyruvate into their mitochondria was also impaired but otherwise was dispensable. This synthetic auxotrophy, i.e., conditional requirement of glutaminase for processes in addition to survival and proliferation, involved support to a progressive expansion of mitochondrial respiration followed by plasma cell differentiation. Surprisingly, impairment of glutaminase and the mitochondrial pyruvate channel decreased IL-21 stimulation of STAT3 phosphorylation as well as interferon stimulation of STAT1 activation. Together, our findings establish not only a powerful collaboration of metabolic pathways in programming increased respiration and the development of Ab-secreting cells, but also reveal modulation of cytokine receptor signaling by metabolism.

immunology↗

bioRxiv2024

Mitochondrial Fatty Acid Synthesis and Mecr Regulate CD4+ T Cell Function and Oxidative Metabolism

SummaryWe show that the mitochondrial fatty acid synthesis gene Mecr shapes CD4+ T cell metabolism and function. It may be targeted in inflammatory diseases and provides rationale to consider the immunological state of patients with mitochondrial disease. Lipid metabolism is fundamental to CD4+ T cell metabolism yet remains poorly understood across subsets. Therefore, we performed targeted in vivo CRISPR/Cas9 screens to identify lipid-associated genes essential for T cell subset functions. These screens established mitochondrial fatty acid synthesis (mtFAS) genes Mecr, Mcat and Oxsm as highly impactful. Of these, the inborn error of metabolism gene Mecr was most dynamically regulated. Effector and memory T cells were reduced in Mecrfl/fl; Cd4cre mice, and MECR was required for activated CD4+ T cells to efficiently proliferate, differentiate, and survive. Mecr-deficient T cells also had decreased mitochondrial respiration, reduced TCA intermediates, and accumulated intracellular iron, which contributed to cell death and sensitivity to ferroptosis. Importantly, Mecr-deficient T cells exhibited fitness disadvantages in inflammatory, tumor, and infection models. mtFAS and MECR thus play important roles in activated T cells and may provide targets to modulate immune functions in inflammatory diseases. The immunological state of MECR- and mtFAS-deficient patients may also be compromised.

immunology↗