Lipid metabolism drives dietary effects on T cell ferroptosis and immunity
TL;DR
Dietary fat composition, particularly PUFA/MUFA ratios, regulates T cell ferroptosis resistance through lipid metabolism. This affects T cell homeostasis, humoral immunity, and anti-tumor responses, including CAR-T therapy. Targeting lipid metabolism could enhance immunotherapy efficacy.
Key Takeaways
- •Dietary fatty acid composition (PUFAs vs MUFAs) directly influences T cell resistance to ferroptosis in both mice and humans
- •Lipid metabolism drives dietary effects on T cell function, impacting follicular helper T cell generation and anti-tumor immunity
- •Ferroptosis regulation in T cells affects humoral immunity and CAR-T therapy outcomes
- •ACSL4 enzyme plays a key mechanistic role in linking dietary lipids to T cell ferroptosis regulation
- •Plasma lipid profiles correlate with human T cell ferroptosis resistance across healthy cohorts
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Abstract
Ferroptosis, a major mechanism of non-apoptotic programmed cell death, critically regulates the homeostasis and functionality of peripheral CD4+ and CD8+ T cells1,2,3,4,5,6. Here we demonstrate that in mouse, resistance of T cells to ferroptosis depends critically on the composition of standard rodent diets, and that dietary effects on ferroptosis (DEFs) have a crucial role in regulation of T cell homeostasis and immune responses. DEFs are microbiota-independent and are driven by variations in dietary polyunsaturated and monounsaturated fatty acids (PUFAs and MUFAs) that lead to variations in abundance of lipid species in lymphoid tissues and T cells. Consistently, ferroptosis resistance of human T cells also correlated with plasma lipid profiles across multiple healthy cohorts, exhibiting negative associations with PUFA/MUFA ratios in major lipid classes. DEFs dictate T cell resilience in the absence of the essential lipid peroxide scavenger GPX4 and broadly modulate T cell-dependent humoral immunity and T cell-mediated anti-tumour immunity, including in chimeric antigen receptor T cell therapy. Mechanistically, ACSL4, which preferentially biosynthezises PUFA-containing phospholipids7, is highly expressed in T cells and underpins DEF-mediated regulation of follicular helper T (TFH) cell generation and function. Our findings reveal the physiological significance of lipid metabolism in driving DEFs in immunity and suggest strategies targeting lipid metabolism to enhance vaccine efficacy and T cell-mediated immunotherapy.
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Data availability
All of the data supporting the findings of this study are available from the corresponding author. RNA-sequencing and scRNA-seq data described in the article have been deposited in the EMBL-EBI database and are accessible via accession number E-MTAB-16107 (bulk RNA-seq) and E-MTAB-16518 (scRNA-seq). Publicly available normalized and batch-adjusted RNA-sequencing data were obtained from GSE137122 (mouse TFH cells and non-TFH cells post-immunization). Source data are provided with this paper.
Code availability
No new algorithms were developed for this Article. Processed data and analysis code are available from the corresponding author.
References
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