Diet-induced dyslipidemia enhances IFN-γ production in mycolic acid-specific T cells and affects mycobacterial...

Dyslipidemia, characterized by altered lipid profiles, influences host immune responses against infections, including Mycobacterium tuberculosis (Mtb). While the effects of dyslipidemia on conventional T cell responses are well documented, its impact on group 1-CD1 restricted T cells, a distinct subset of lipid antigen-specific unconventional T cells, during Mtb infection remains unclear. In this study, we developed a double-transgenic mouse model expressing human group 1 CD1 (hCD1Tg) and mycolic acid (MA)-specific CD1b-restricted T cell receptor (DN1Tg) in a Rag-deficient and low-density lipoprotein receptor-deficient background to investigate how diet-induced dyslipidemia affects the functionality of MA-specific T cells and their role in anti-Mtb immunity. We found that diet-induced dyslipidemia led to increased IFN-γ production by MA-specific T cells, which promoted mycobacterial clearance in vitro. Mechanistically, this enhanced IFN-γ production was associated with increased TCR signaling and enhanced glycolysis in DN1 T cells, rather than changes in antigen presentation by dendritic cells. However, dyslipidemia also increased apoptosis in DN1 T cells, which may have impaired their ability to control mycobacterial infection in vivo, resulting in reduced bacterial clearance. These findings highlight a complex interplay between diet-induced dyslipidemia and lipid antigen-specific T-cell responses in Mtb infection, providing insights for potential therapeutic strategies to mitigate dyslipidemia-induced changes in T-cell functions.