Inherent metabolic preferences differentially regulate the sensitivity of Th1 and Th2 cells to ribosome‐inhibiting antibiotics

IF 4.9 3区 医学 Q2 IMMUNOLOGY Immunology Pub Date : 2024-09-12 DOI:10.1111/imm.13860
Neha Jawla, Raunak Kar, Veena S. Patil, G. Aneeshkumar Arimbasseri
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Abstract

Mitochondrial translation is essential to maintain mitochondrial function and energy production. Mutations in genes associated with mitochondrial translation cause several developmental disorders, and immune dysfunction is observed in many such patients. Besides genetic mutations, several antibiotics targeting bacterial ribosomes are well‐established to inhibit mitochondrial translation. However, the effect of such antibiotics on different immune cells is not fully understood. Here, we addressed the differential effect of mitochondrial translation inhibition on different subsets of helper T cells (Th) of mice and humans. Inhibition of mitochondrial translation reduced the levels of mitochondrially encoded electron transport chain subunits without affecting their nuclear‐encoded counterparts. As a result, mitochondrial oxygen consumption reduced dramatically, but mitochondrial mass was unaffected. Most importantly, we show that inhibition of mitochondrial translation induced apoptosis, specifically in Th2 cells. This increase in apoptosis was associated with higher expression of Bim and Puma, two activators of the intrinsic pathway of apoptosis. We propose that this difference in the sensitivity of Th1 and Th2 cells to mitochondrial translation inhibition reflects the intrinsic metabolic demands of these subtypes. Though Th1 and Th2 cells exhibit similar levels of oxidative phosphorylation, Th1 cells exhibit higher levels of aerobic glycolysis than Th2 cells. Moreover, Th1 cells are more sensitive to the inhibition of glycolysis, while higher concentrations of glycolysis inhibitor 2‐deoxyglucose are required to induce cell death in the Th2 lineage. These observations reveal that selection of metabolic pathways for substrate utilization during differentiation of Th1 and Th2 lineages is a fundamental process conserved across species.
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固有的代谢偏好对 Th1 和 Th2 细胞对核糖体抑制抗生素的敏感性有不同的调节作用
线粒体翻译对维持线粒体功能和能量生产至关重要。与线粒体翻译有关的基因突变会导致多种发育障碍,许多此类患者还会出现免疫功能障碍。除基因突变外,几种针对细菌核糖体的抗生素已被证实可抑制线粒体翻译。然而,这些抗生素对不同免疫细胞的影响还不完全清楚。在这里,我们研究了线粒体翻译抑制对小鼠和人类辅助性 T 细胞(Th)不同亚群的不同影响。抑制线粒体翻译会降低线粒体编码的电子传递链亚基的水平,而不会影响核编码的相应亚基。因此,线粒体耗氧量急剧下降,但线粒体质量不受影响。最重要的是,我们发现抑制线粒体翻译会诱导细胞凋亡,特别是在 Th2 细胞中。细胞凋亡的增加与 Bim 和 Puma(两种细胞凋亡内在途径的激活剂)的高表达有关。我们认为 Th1 和 Th2 细胞对线粒体翻译抑制的敏感性差异反映了这些亚型的内在代谢需求。虽然 Th1 和 Th2 细胞的氧化磷酸化水平相似,但 Th1 细胞的有氧糖酵解水平高于 Th2 细胞。此外,Th1 细胞对糖酵解抑制更敏感,而糖酵解抑制剂 2-deoxyglucose 的浓度更高,才能诱导 Th2 系细胞死亡。这些观察结果表明,在 Th1 和 Th2 系的分化过程中选择底物利用的代谢途径是一个跨物种的基本过程。
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来源期刊
Immunology
Immunology 医学-免疫学
CiteScore
11.90
自引率
1.60%
发文量
175
审稿时长
4-8 weeks
期刊介绍: Immunology is one of the longest-established immunology journals and is recognised as one of the leading journals in its field. We have global representation in authors, editors and reviewers. Immunology publishes papers describing original findings in all areas of cellular and molecular immunology. High-quality original articles describing mechanistic insights into fundamental aspects of the immune system are welcome. Topics of interest to the journal include: immune cell development, cancer immunology, systems immunology/omics and informatics, inflammation, immunometabolism, immunology of infection, microbiota and immunity, mucosal immunology, and neuroimmunology. The journal also publishes commissioned review articles on subjects of topical interest to immunologists, and commissions in-depth review series: themed sets of review articles which take a 360° view of select topics at the heart of immunological research.
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