High-fat diet promotes exhaustion-associated T-cell remodeling across vascular and lymphoid tissues in atherosclerosis-prone mice
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Background
Atherosclerosis is a chronic inflammatory disease driven by lipid accumulation and immune dysregulation. How chronic dietary lipid exposure reshapes T-cell states across vascular and lymphoid tissues, and whether these changes resolve after dietary normalization, remains incompletely defined. This study examined diet-associated T-cell remodeling and the contribution of macrophage-mediated stimulation
Methods
ApoE-deficient mice received a vegetarian diet (VD) or high-fat diet (HFD) for 12 or 24 weeks; a dietary reversal group received HFD for 12 weeks followed by VD for 12 weeks. CD45-positive cells from aorta, blood, spleen, lymph nodes, and bone marrow underwent single-cell RNA sequencing with matched T-cell receptor sequencing. T-cell states were annotated using canonical markers, and exhaustion-and naive-associated transcriptional programs were quantified using UCell scores. Analyses assessed T-cell composition, clonal expansion, and predicted macrophage–T-cell communication, with splenic flow-cytometric validation.
Results
HFD was associated with enrichment of exhaustion-associated states, with the highest exhaustion scores in the aorta. At 24 weeks, the pooled exhausted-cell proportion was 15.7% under HFD versus 10.6% under VD. Dietary reversal restored this proportion to 10.6%, while residual transcriptional changes persisted in a tissue-dependent manner. Flow cytometry corroborated increased inhibitory receptor expression and co-expression. Aortic macrophages exhibited inflammatory and antigen-presentation programs alongside increased predicted communication with T cells. Aortic T-cell activation and clonal expansion accompanied these changes, and clonotype size correlated with exhaustion score (Spearman correlation coefficient = 0.57, p = 0.029).
Conclusion
Chronic HFD is associated with multicompartment T-cell remodeling, with prominent vascular exhaustion-associated programs and tissue-dependent recovery after dietary normalization. These findings suggest that dietary lipid exposure may leave a durable adaptive immune imprint across organs during atherosclerosis.
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High-fat diet promotes exhaustion-associated T-cell remodeling across vascular and lymphoid tissues in atherosclerosis-prone mice https://www.biorxiv.org/content/10.64898/2026.11.03.763491v1
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High-fat diet promotes exhaustion-associated T-cell remodeling across vascular and lymphoid tissues in atherosclerosis-prone mice https://www.biorxiv.org/content/10.64898/2026.11.03.763491v1
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