The generation of senescent-like CD4+ EMRA T cells in T2D and their contribution to poor COVID-19 vaccine responses
The generation of senescent-like CD4+ EMRA T cells in T2D and their contribution to poor COVID-19 vaccine responses
复制标题
T2D 中衰老样 CD4 EMRA T 细胞的产生及其对 COVID-19 疫苗反应不佳的影响
DOI：
10.1093/discim/kyad026
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Garrod-Ketchley C
中科院分区：
文献类型：
--
作者：
Garrod-Ketchley C
CD4+T细胞对于抵御病毒病原体，如SARS-CoV-2至关重要。然而，功能障碍的CD4+EMRA亚群的增加可能会阻碍对病毒的免疫反应。我们在这里表明，随着血糖的升高，CD+EMRA增加，例如患有T2D的人，这会改变线粒体功能，导致CD+T细胞的分化，降低对新冠肺炎疫苗的免疫反应。在高糖和低糖培养液中分别加入鱼藤酮和MitoQ，检测CD4+T细胞的衰老、胰岛素动力学和线粒体功能。血清标本用于检测循环炎症反应和SARS-CoV-2抗体。患有T2D的患者有CD4+EMRA T细胞的表达增加，其出现与血糖值升高相关。T2D组显示线粒体膜电位降低，mtROS生成增加。这些结果被用高糖培养基来模拟，这种培养基能加速CD4+T细胞分化并降低基质金属蛋白酶。患有T2D(非高血糖和高血糖)的人改变了炎症介质的表达。新冠肺炎多肽对CD4+EMRA细胞无反应，患有T2D的患者对SARS-CoV-2S1刺突蛋白的T细胞和抗体反应降低。我们已经证明了衰老的类CD4+EMRA影响SARS-CoV-2中的病毒反应，并且CD4+EMRAs可能是由于环境葡萄糖增加而导致的线粒体动力学故障引起的。需要进一步的研究来确定血糖增加与CD4+EMRA形成的直接联系。
CD4+ T cells are essential for protection from viral pathogens, such as SARS-CoV-2. However, an increase in the dysfunction CD4+ EMRA subset is likely to hinder the immune response towards viruses. We show here that CD4+ EMRAs are increased with elevated blood glucose, such as people living with T2D, which alters mitochondrial function and causes the differentiation of CD4+ T cells, reducing the immune response to COVID-19 vaccination. CD4+ T cells were examined for senescence, their insulin dynamics, and mitochondrial function afterin vitroculture of high and low glucose media, with or without rotenone or mitoQ. Serum samples were used to assess circulating inflammation and IgG antibodies to SARS-CoV-2. People living with T2D had increased expression of CD4+ EMRA T cells, the appearance of which correlated with increasing blood glucose values. The T2D cohort showed a reduced mitochondrial membrane potential (MMP) and increased mtROS production. These results were mimicked using high-glucose media that accelerated CD4+ T cell differentiation and reduced MMP. People living with T2D (non-hyperglycaemic and hyperglycaemic) had altered expression of inflammatory mediators. CD4+ EMRA cells did not respond to COVID-19 peptides, and people with T2D had a reduced T cell and antibody response to SARS-CoV-2 S1 spike protein. We have shown that senescent-like CD4+ EMRA influence the viral response in SARS-CoV-2 and that CD4+ EMRAs may arise from faulty mitochondrial dynamics due to increased environmental glucose. Further study is required to determine the direct link increased glucose has with CD4+ EMRA formation.