Glycolysis: An early marker for vancomycin-specific T-cell activation
Glycolysis: An early marker for vancomycin-specific T-cell activation
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DOI：
10.1111/cea.14423
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发表时间：
2024-01-04
影响因子：
6.1
通讯作者：
Naisbitt，Dean J.
中科院分区：
文献类型：
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作者：
Gardner，Joshua;Hammond，Sean;Naisbitt，Dean J.
背景万古霉素是一种用于治疗革兰氏阳性菌感染的糖肽类抗生素，在HLA-A *32：01表达个体中与药物反应伴嗜酸性粒细胞增多和全身症状（DRESS）有关。这与T淋巴细胞的活化有关，其中糖酵解已被分离为抗原刺激后的燃料途径。然而，支持药物反应性T细胞活化的代谢过程目前尚不明确，可能有助于阐明引发药物超敏反应或耐受性途径所需的能量条件。在这里，我们试图在DRESS发病机制的背景下，使用万古霉素作为模型化合物和从健康供体和万古霉素超敏患者中产生的药物反应性T细胞克隆（TCC）来阐明药物特异性T细胞活化中涉及的免疫和代谢途径。采用Seahorse XFe 96分析仪测定胞外酸化率（ECAR）作为糖酵解功能的指标。此外，T细胞增殖和细胞因子释放（IFN-γ）测定被用来关联的T细胞活化的生物能量特性与体外assays.ResultsModel T细胞刺激诱导非特异性T细胞活化，其特征在于立即增强ECAR和ATP生产率（JATPglyc）。当万古霉素反应性TCC暴露于药物时，存在剂量依赖性和药物特异性糖酵解偏移。在增殖和细胞因子读数中，万古霉素反应性TCC未表现出与结构相似化合物的T细胞交叉反应性。然而，在分析能量反应时观察到交叉反应性;还发现既往对万古霉素具有特异性的TCC在暴露于替考拉宁后显示糖酵解转换。TCC的糖酵解活化是HLA限制的，因为暴露于HLA阻断减弱了糖酵解induction.ConclusionThese研究描述了万古霉素暴露后的CD 4+和CD 8 + T细胞的糖酵解移位。由于在替考拉宁中观察到类似的糖酵解转换，而替考拉宁不激活T细胞，因此T细胞激活的主开关可能位于代谢信号传导的上游。
BackgroundVancomycin, a glycopeptide antibiotic used for Gram‐positive bacterial infections, has been linked with drug reaction with eosinophilia and systemic symptoms (DRESS) in HLA‐A*32:01‐expressing individuals. This is associated with activation of T lymphocytes, for which glycolysis has been isolated as a fuel pathway following antigenic stimulation. However, the metabolic processes that underpin drug‐reactive T‐cell activation are currently undefined and may shed light on the energetic conditions needed for the elicitation of drug hypersensitivity or tolerogenic pathways. Here, we sought to characterise the immunological and metabolic pathways involved in drug‐specific T‐cell activation within the context of DRESS pathogenesis using vancomycin as model compound and drug‐reactive T‐cell clones (TCCs) generated from healthy donors and vancomycin‐hypersensitive patients.MethodsCD4+ and CD8+ vancomycin‐responsive TCCs were generated by serial dilution. The Seahorse XFe96Analyzer was used to measure the extracellular acidification rate (ECAR) as an indicator of glycolytic function. Additionally, T‐cell proliferation and cytokine release (IFN‐γ) assay were utilised to correlate the bioenergetic characteristics of T‐cell activation with in vitro assays.ResultsModel T‐cell stimulants induced non‐specific T‐cell activation, characterised by immediate augmentation of ECAR and rate of ATP production (JATPglyc). There was a dose‐dependent and drug‐specific glycolytic shift when vancomycin‐reactive TCCs were exposed to the drug. Vancomycin‐reactive TCCs did not exhibit T‐cell cross‐reactivity with structurally similar compounds within proliferative and cytokine readouts. However, cross‐reactivity was observed when analysing energetic responses; TCCs with prior specificity for vancomycin were also found to exhibit glycolytic switching after exposure to teicoplanin. Glycolytic activation of TCC was HLA restricted, as exposure to HLA blockade attenuated the glycolytic induction.ConclusionThese studies describe the glycolytic shift of CD4+ and CD8+ T cells following vancomycin exposure. Since similar glycolytic switching is observed with teicoplanin, which did not activate T cells, it is possible the master switch for T‐cell activation is located upstream of metabolic signalling.