Hyperlipidemia elicits an IFN-based CD4+ T cell response
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ABSTRACT:
PROVIDER: PRJNA808093 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18061511.fastq.gz | Fastqsanger.gz | |||
| SRR18061512.fastq.gz | Fastqsanger.gz | |||
| SRR18061513.fastq.gz | Fastqsanger.gz | |||
| SRR18061514.fastq.gz | Fastqsanger.gz | |||
| SRR18061515.fastq.gz | Fastqsanger.gz |
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Project description: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.
2023-03-29 | GSE196970 | GEO
Project description:Hyperlipidemia elicits an IFN-based CD4+ T cell response: a key role for VLDL
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Project description: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.
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Project description: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 TNFα and interferon-γ (IFN-γ). Gene set enrichment analysis identified IFN-γ-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-γ-mediated signaling. In conclusion, hyperlipidemia, and especially its VLDL component induces an atypicial Th1 response in CD4+ T-cells.
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Project description:Hyperlipidemia elicits an atypical, Th1 like CD4+ T cell response: a key role for VLDL
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Project description:CD4+ T cells are indispensable for optimal immunity to Mycobacterium tuberculosis (M.tb), a virulent pathogen that triggers tuberculosis (TB), in humans, as evidenced by studies of patients with CD4+ T lymphocytopenia. M.tb-specific human CD4+ T cells are known to polarize toward an IFN-γ-producing, T-bet+RORγT+ TH1* memory phenotype. We report that inherited deficiency of the human lymphocytic surface receptor LY9 (SLAMF3, CD229) underlies TB, but not BCG disease, due to dysfunction of TH1* cells. We find autosomal recessive, complete LY9 deficiency in three unrelated patients with TB and one asymptomatic relative, but not in patients with other infections studied, including patients with BCG disease, and in less than 10-5 individuals in the general population. TH1* cells in LY9-deficient individuals show selective impairment in IFN-γ production. By contrast, LY9 deficiency does not disrupt the development or function of leukocyte subsets other than TH1* cells, including TH1 cells. Mechanistically, LY9 polarizes naïve CD4+ T cells toward memory TH1* cells by inducing T-bet via SAP, and RORγT without SAP. Among CD4+ T cell subsets, TH1* cells express LY9 at the highest level. Finally, LY9 costimulation enhances TCR-driven IFN-γ production of memory TH1*, but not TH1, cells in a T-cell-intrinsic manner via NFAT1 and RORγT. Human LY9 is thus required for an optimal TH1*-cell- and IFN-γ-dependent protective immunity to M.tb. These findings, in turn, suggest that, without fully functional TH1* cells, TH1 cells and other T cell subsets may not be sufficient for optimal protective immunity to M.tb in humans.
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