合成营养缺陷模型揭示谷氨酰胺分解调控浆细胞生成与抗体亲和成熟
Synthetic auxotrophy reveals metabolic regulation of plasma cell generation, affinity maturation, and cytokine receptor signaling
研究利用合成营养缺陷（synthetic auxotrophy）策略，发现严格限制谷氨酰胺供应会降低B细胞增殖及向浆细胞的分化，但谷氨酰胺分解仅在特定条件下对B细胞及抗体应答关键。编码淋巴细胞主要谷氨酰胺酶的Gls基因，只有当小鼠B细胞的葡萄糖摄取或线粒体丙酮酸输入同时受损时，才在初次和再次抗NP抗体应答中发挥作用，否则可有可无。这种条件性依赖涉及支持线粒体呼吸的逐步扩张，进而推动浆细胞分化。谷氨酰胺酶与线粒体丙酮酸通道同时受损，还会降低IL-21刺激的STAT3磷酸化以及干扰素刺激的STAT1活化。研究提示代谢通路协同编程呼吸增强与抗体分泌细胞发育，并揭示代谢对细胞因子受体信号的调节。
来源：eLife · doi.org
The proliferation and development of activated B lymphocytes into antibody (Ab)-secreting plasma cells are critical determinants of humoral immunity and sustain certain autoimmune diseases. Specific pathways and substrate supplies in intermediary metabolism influence lymphocyte differentiation and function. We now show that although stringent restriction of glutamine supply decreases B cell proliferation and differentiation into plasma cells, glutaminolysis – a major metabolic use of this amino acid – was only conditionally crucial in B cells and the Ab responses derived from them. 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 mouse B cells or pyruvate into their mitochondria was also impaired. Otherwise, it was dispensable. This synthetic auxotrophy, that is, the conditional requirement of glutaminase for processes in addition to survival, involved supporting 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 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.