Hyperlipidemia elicits an atypical, Th1 like CD4+ T cell response: a key role for VLDL

Hyperlipidemia and T cell driven inflammation are important drivers of atherosclerosis, the principal underlying cause of cardiovascular disease. Here, we applied an in-depth multi-omics approach to detail the effects of hyperlipidemia on T cells. In vitro, exposure of CD4+ T cells to very low-density lipoprotein (VLDL), but not to low-density lipoprotein (LDL) resulted in upregulation of Th1 associated pathways, suggesting that VLDL serves as the main lipid component driving hyperlipidemia induced T cell activation. To further detail this response in vivo, T-cells of ldlr-/- fed a normal cholesterol or high cholesterol diet, which develop a strong increase in VLDL cholesterol and triglyceride levels, were investigated. CD4+ T cells of hyperlipidemic ldlr-/- mice exhibited an increased expression of CXC-chemokine receptor 3 (CXCR3) and produced more TNFa and interferon-? (IFN-?). Gene set enrichment analysis identified IFN-?-mediated signaling as the most upregulated pathway in hyperlipidemic T cells. However, the classical Th1 associated transcription factor profile with strong upregulation of Tbet and downregulation of Gata3 was not observed. Hyperlipidemia did not affect levels of the CD4+ T-cell's metabolites involved in glycolysis or other canonical metabolic pathways but enhanced amino acids levels. However, CD4+ T-cells of hyperlipidemic mice showed increased cellular cholesterol accumulation and an increased arachidonic acid (AA) to docosahexaenoic acid (DHA) ratio, which was associated with T cell activation and IFN-?-mediated signaling. In conclusion, hyperlipidemia, and especially its VLDL component induces an atypicial Th1 response in CD4+ T-cells. Overall design: Comparison of gene expression in human CD4+ T cells exposed to LDL (n=3) or VLDL (n=3) with untreated cells (n=3)