Type 2 diabetes (T2D) increases the risk of complications during respiratory viral infections and individuals with T2D fail to mount robust T helper 1 (TH1) 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 TH1 responses. In individuals with T2D and severe COVID-19, the authors note a lower proportion of TH1 cells. In mice, if T2D was induced before infection with influenza, there was impaired viral control and fewer TH1 cells. Individuals with T2D were split into groups based on their glycemic control, and those with poorly controlled T2D (PC-T2D) had fewer circulating TH1 cells than healthy control individuals or those with well-controlled T2D. Only naive T cells from individuals with PC-T2D had impaired differentiation to TH1 cells when cultured under polarizing conditions. LPO was higher in TH1 cells from individuals with PC-T2D and an LPO inhibitor could restore TH1 cell differentiation of naive PC-T2D T cells and increase TH1 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 TH1 differentiation of PC-T2D T cells.

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