T cell cholesterol efflux suppresses apoptosis and senescence and increases atherosclerosis in middle aged mice

Bazioti, Venetia; Rose, Anouk M. La; Maassen, Sjors; Bianchi, Frans; Boer, Rinse de; Halmos, Benedek; Dabral, Deepti; Guilbaud, Emma; Svendsen, Arthur Flohr; Groenen, Anouk G.; Marmolejo-Garza, Alejandro; Koster, Mirjam H.; Kloosterhuis, Niels J.; Havinga, Rick; Pranger, Alle; Langelaar-Makkinje, Miriam; Bruin, Alain de; Sluis, Bart van de; Kohan, Alison B.; Yvan‐Charvet, Laurent; Bogaart, Geert van den; Westerterp, Marit

doi:10.1038/s41467-022-31135-4

Cited by 35 publications

(33 citation statements)

References 82 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Hence, other factors contribute to the loss or differentiation of naïve T cells in AD. Studies from atherosclerosis, another age-related disease, show that accumulation of cholesterol in T cells induces T cell aging phenotype, including less frequent naïve T cells ( 69 ). Interestingly, CD8 virtual memory T cells accumulate with age and upregulate lipid rafts ( 6 , 70 ).…”

Section: Naïve/memory T Cells Imbalance and Admentioning

confidence: 99%

T cell aging and Alzheimer’s disease

Guo

Gould³

et al. 2023

Front. Immunol.

View full text Add to dashboard Cite

The brain has long been considered an immune-privileged organ due to the presence of the blood-brain barrier (BBB). However, recent discoveries have revealed the underestimated role of T cells in the brain through the meningeal lymphatic system. Age is the primary risk factor for Alzheimer’s disease (AD), resulting in marked age-dependent changes in T cells. Manipulating peripheral T cell immune response has been shown to impact AD, but the relationship between T cell aging and AD remains poorly understood. Given the limited success of targeting amyloid beta (Aβ) and the growing evidence of T cells’ involvement in non-lymphoid organ aging, a deeper understanding of the relationship between T cells and AD in the context of aging is crucial for advancing therapeutic progress. In this review, we comprehensively examine existing studies on T cells and AD and offer an integrated perspective on their interconnections in the context of aging. This understanding can inform the development of new interventions to prevent or treat AD.

show abstract

Section: Naïve/memory T Cells Imbalance and Admentioning

confidence: 99%

T cell aging and Alzheimer’s disease

Guo

Gould³

et al. 2023

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…Surprisingly, the total number of T cells had decreased, which was due to increased T cell apoptosis and senescence, especially in middle aged mice, which also displayed a reduction in atherosclerosis. 38 …”

Section: Discussionmentioning

confidence: 99%

Hyperlipidaemia elicits an atypical, T helper 1–like CD4+ T-cell response: a key role for very low-density lipoprotein

Vos

Bosmans

et al. 2023

European Heart Journal Open

View full text Add to dashboard Cite

Aims Hyperlipidemia and T cell driven inflammation are important drivers of atherosclerosis, the main underlying cause of cardiovascular disease. Here, we detailed the effects of hyperlipidemia on T cells. Methods and results In vitro, exposure of human and murine CD4+ T cells to very low-density lipoprotein (VLDL), but not to low-density lipoprotein (LDL) resulted in upregulation of Th1 associated pathways. VLDL was taken up via a CD36-dependent pathway and resulted in membrane stiffening and a reduction in lipid rafts. To further detail this response in vivo, T cells of mice lacking the LDL receptor (LDLr), which develop a strong increase in VLDL cholesterol and triglyceride levels upon high cholesterol feeding were investigated. CD4+ T cells of hyperlipidemic Ldlr-/- mice exhibited an increased expression of the C-X-C-chemokine receptor 3 (CXCR3) and produced more 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 Il12rb2 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 cholesterol accumulation and an increased arachidonic acid (AA) to docosahexaenoic acid (DHA) ratio, which was associated with inflammatory T cell activation. Conclusions Hyperlipidemia, and especially its VLDL component induces an atypical Th1 response in CD4+ T cells. Underlying mechanisms include CD36 mediated uptake of VLDL, and an altered AA/DHA ratio.

show abstract

“…Moreover, aging plaque T cells can accumulate cholesterol, a mechanism that has been suggested to promote T-cell apoptosis and senescence, while attenuating atherosclerosis. 76 Our transcriptomic analysis identified Cpne7, the gene that encodes for copine-7, a member of the copine family of proteins, to be downregulated in Mif-deficient 24-week HFD mice and highly upregulated in the 42-week Mif-deficient group. Copins are a poorly characterized group of Ca 2+ -dependent, phospholipid-binding proteins that are thought to play a role in membrane-trafficking processes.…”

Section: Discussionmentioning

confidence: 99%