Type 2 diabetes (T2D) increases the risk of complications during respiratory viral infections and individuals with T2D fail to mount robust T helper 1 (T_H1) responses. In Cell Metabolism, Gray et al. find that hyperglycemia drives mitochondrial dysfunction and lipid peroxidation (LPO) that leads to STAT4 degradation and results in diminished T_H1 responses. In individuals with T2D and severe COVID-19, the authors note a lower proportion of T_H1 cells. In mice, if T2D was induced before infection with influenza, there was impaired viral control and fewer T_H1 cells. Individuals with T2D were split into groups based on their glycemic control, and those with poorly controlled T2D (PC-T2D) had fewer circulating T_H1 cells than healthy control individuals or those with well-controlled T2D. Only naive T cells from individuals with PC-T2D had impaired differentiation to T_H1 cells when cultured under polarizing conditions. LPO was higher in T_H1 cells from individuals with PC-T2D and an LPO inhibitor could restore T_H1 cell differentiation of naive PC-T2D T cells and increase T_H1 cell differentiation and viral control in mice with T2D. LPO induced the carbonylation of STAT4, which accelerated its degradation. The increased LPO levels in T cells from PC-T2D individuals was driven by increases in mitochondrial reactive oxygen species (mROS) caused by impaired mitochondrial biogenesis and increased fatty acid synthesis (FAS); scavenging mROS or blocking FAS could restore T_H1 differentiation of PC-T2D T cells.

Original reference: Cell Metab. https://doi.org/10.1016/j.cmet.2024.10.004 (2024)

2 型糖尿病 （T2D） 会增加呼吸道病毒感染期间出现并发症的风险，并且 T2D 患者无法产生强大的辅助性 T 1 （T_H1） 反应。在《细胞代谢》中，Gray 等人发现，高血糖会驱动线粒体功能障碍和脂质过氧化 （LPO），从而导致 STAT4 降解并导致 T_H1 反应减少。在 T2D 和严重 COVID-19 的个体中，作者注意到 T_H1 细胞的比例较低。在小鼠中，如果在感染流感之前诱导 T2D，则病毒控制受损，T_H1 细胞减少。根据 T2D 患者的血糖控制情况将其分为几组，T2D 控制不佳的个体 （PC-T2D） 的循环 T_H1 细胞少于健康对照个体或 T2D 控制良好的个体。在极化条件下培养时，只有来自 PC-T2D 个体的幼稚 T 细胞与 T_H1 细胞的分化受损。LPO 在 PC-T2D 个体的 T_H1 细胞中较高，LPO 抑制剂可以恢复幼稚 PC-T2D T 细胞的 T_H1 细胞分化，并增加 T2D 小鼠的 T_H1 细胞分化和病毒控制。LPO 诱导 STAT4 的羰基化，从而加速其降解。PC-T2D 个体 T 细胞中 LPO 水平的增加是由线粒体生物发生受损和脂肪酸合成增加 （FAS） 引起的线粒体活性氧 （mROS） 增加驱动的;清除 mROS 或阻断 FAS 可以恢复 PC-T2D T 细胞的 T_H1 分化。

原始参考：Cell Metab.https://doi.org/10.1016/j.cmet.2024.10.004 （2024）