Hyperlipidemia elicits an IFN-based CD4+ T cell response

Hyperlipidemia is accompanied by increased systemic inflammation. However, how hyperlipidemia affects T cell biology is still unclear. We aimed to detail the effects of hyperlipidemia on the T cell’s transcriptome, metabolome and lipidome. Low-density lipoprotein receptor-deficient (LDLR-/-) mice were subjected to a 0.15% high cholesterol diet (HCD), a normal chow diet (NCD) and T cells were analyzed. Hyperlipidemia induced an increase in CXCR3 on and IFN in CD4+ T cells, which was accompanied by transcriptomic changes in interleukin-mediated JAK/STAT signaling, interferon-γ signaling and a general pro-inflammatory immune response, suggesting that hyperlipidemia induces a Th1-like response. In these T cells, hyperlipidemia did not affect levels of metabolites involved in glycolysis or fatty acid oxidation, but enhanced amino acids levels. CD4+ T-cells of mice fed a HCD exhibited increased cellular cholesterol accumulation and an increased arachidonic acid (AA) to Docosahexaenoic acid (DHA) ratio, which was associated with T cell activation and IFN signaling. In vitro, T cell exposure to VLDL, but not LDL phenocopied these results. The effect of hyperlipidemia on T cell activation is reversible as transcriptional- and lipid profiles in LDLr-/ mice normalized 6 weeks after switching the HCD to NCD. In conclusion, hyperlipidemia induces a Th1-like response in CD4+ T cells, which is associated with an AA/DHA ratio in these cells. VLDL, but not LDL is the main lipid component driving hyperlipidemia induced T cell activation. Comparison of gene expression in CD4+ T cells from mice fed a normal cholesterol diet (n=5), a high cholesterol diet (n=6), or that switched from a high cholesterol diet to a normal cholesterol diet (n=6)