Hyperglycaemia in type 2 diabetes impairs T-helper 1 differentiation through elevated lipid peroxidation

Abstract

Patients with Type 2 diabetes (T2D) are more vulnerable to severe respiratory viral infections, particularly against SARS-CoV2 and Influenza viruses. Although COVID-19 vaccines have been found to reduce disease severity, T2D patients often display impaired vaccination responses. This thesis aimed to investigate the vaccine response in T2D patients by comparing the effectiveness of novel mRNA (BNT162b2) and inactivated (CoronaVac) COVID- 19 vaccine platforms alongside the impact of T2D on anti-viral cellular T cell responses. Cellular and humoral responses were evaluated in a first cohort of healthy controls (HC) and T2D patients who received either mRNA or inactivated vaccines. Whereas the metabolic parameters and anti-viral functionality of T cells was assessed using a second cohort of T2D patients with varying glycaemic control alongside in vivo and in vitro models of T2D. The results showed that after a single dose of BNT162b2, humoral responses were comparable between T2D patients and HC, but T2D patients displayed impaired Th1 differentiation in CD4+ T cell responses. However, after a full 2-dose vaccine course, immune responses induced by BNT162b2 were similar between T2D patients and HC. In contrast, after a full course of CoronaVac, T2D patients exhibited impaired humoral and CD4+ T cell vaccine induced responses. Further investigation revealed that both T2D patients and murine models of T2D displayed impaired Th1 differentiation, which was attributed to intrinsic metabolic perturbations in CD4+ T cells caused by hyperglycaemia. Hyperglycaemia induced mitochondrial dysfunction and fatty acid synthesis in CD4+ T cells, leading to oxidative stress and lipid accumulation, ultimately promoting lipid peroxidation which was found to impair Th1 differentiation. However the inhibition of lipid peroxidation restored anti-viral CD4+ T cell function in T2D patients and mice. These findings have significant implications, notably as T2D influences the effectiveness of COVID-19 vaccines depending on their platform, future considerations should be made regarding the specific vaccine regiments recommended for T2D patients. Additionally, this study identified a mechanism through which poor glycaemic control in T2D patients affects anti-viral cellular immunity, highlighting lipid peroxidation as a potential therapeutic target to mitigate the elevated severity of respiratory infections in T2D patients.