The generation of senescent-like CD4+ EMRA T cells in T2D and their contribution to poor COVID-19 vaccine responses

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Abstract 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 after in vitro culture 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 and increased mtROS production. These results were mimicked using high glucose media which 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.