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Diet-induced dyslipidemia leads to enhanced IFN-g production by mycolic acid-specific T cells

ABSTRACT: Diet-induced dyslipidemia, characterized by elevated plasma LDL-cholesterol levels, has been shown to affect host defense against infections, including Mycobacterium tuberculosis (Mtb). Although the impact of diet-induced dyslipidemia on conventional T cell functions is well studied, its influence on group 1-restricted T cells during Mtb infection is very limited. In this study, we generated a unique double-transgenic mouse model expressing human CD1 and mycolic acid (MA)-specific CD1b-restricted T cell receptor in a Rag-deficient and low-density lipoprotein receptor-deficient background to investigate how diet-induced dyslipidemia impacts functionality of MA-specific T cells and its effect on anti-Mtb immunity. While dyslipidemia augmented IFN-g production by MA-specific T cells, it paradoxically led to increased apoptosis and thus compromised their ability to restrict Mtb growth in vivo. These findings may elucidate the complex interplay between diet-induced dyslipidemia and lipid antigen-specific T-cell responses in the context of Mtb infection, offering insights that could inform potential therapeutic approaches addressing dyslipidemia-induced changes in T-cell functions.

ORGANISM(S): Mus musculus

PROVIDER: GSE277479 | GEO | 2025/08/13

REPOSITORIES: GEO

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Project description:Mycobacterium tuberculosis has a complex cell envelope that is remodelled throughout infection to respond and survive the hostile and variable intracellular conditions within the host. Despite the importance of cell wall homeostasis in pathogenicity, little is known about the environmental signals and regulatory networks controlling cell wall biogenesis in mycobacteria. The mycolic acid desaturase regulator (MadR) is a transcriptional repressor responsible for regulation of the essential aerobic desaturases desA1 and desA2 that are differentially regulated throughout infection along with mycolate modification genes and thus, likely involved in mycolic acid remodelling. Here we generated a madR null mutant in M. smegmatis that exhibited traits of an impaired cell wall with increased permeability, susceptibility to rifampicin and cell surface disruption as a consequence of desA1/desA2 dysregulation. Analysis of mycolic acids revealed the presence of a highly desaturated mycolate in the null mutant that exists in relative trace amounts in the wildtype, but increases in abundance upon cell surface disruption as a result of relieved repression on the desA1/desA2 promoters. Transcriptomic profiling confirmed MadR as a cell surface disruption responsive regulator of desA1/desA2 and further implicating it in the control of bespoke β-oxidation pathways and transport evolutionarily diversified subnetworks associated with virulence. In vitro characterisation of MadR using electromobility shift assays and analysis of binding affinities is suggestive of a unique acyl-CoA pool sensing mechanism, whereby MadR is able to bind a range of acyl-CoA but MadR repression of desA1/desA2 promoters is only relieved upon binding of saturated acyl-CoA of chain length C16-C24. We propose this acyl effector ligand mechanism as distinct to other regulators of mycolic acid biosynthesis or fatty acid desaturases and places MadR as the key regulatory checkpoint that coordinates mycolic acid remodelling in response to host derived cell surface perturbation

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Diet-induced dyslipidemia leads to enhanced IFN-g production by mycolic acid-specific T cells

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