The low-density lipoprotein receptor-mTORC1 axis coordinates CD8+ T cell activation

Area of Science:

• Immunology
• Cell Biology
• Metabolic Research

Background:

• T cell activation is critically dependent on intracellular cholesterol levels.
• Extracellular cholesterol uptake pathways, like the low-density lipoprotein receptor (LDLR), may influence T cell immunometabolism.

Purpose of the Study:

• To investigate the role of extracellular cholesterol, specifically via the LDLR pathway, in T cell activation.
• To elucidate the impact of LDLR-mediated cholesterol uptake on CD8+ T cell immunometabolic responses.

Main Methods:

• Proteomics and gene expression profiling to analyze LDLR pathway components.
• Immunophenotyping to assess T cell activation, proliferation, and cytokine production.
• Studies using wild-type (WT) and LDLR-deficient (Ldlr-/-) mice, and human familial hypercholesterolemia (FH) patient cells.

Main Results:

• LDLR expression is upregulated in activated CD8+ T cells compared to CD4+ T cells.
• CD8+ T cells from Ldlr-/- mice exhibited reduced proliferation and cytokine (IFNγ, Granzyme B, Perforin) production.
• Impaired cholesterol routing to lysosomes and reduced mTORC1 activation were observed in LDLR-deficient CD8+ T cells.
• Human CD8+ T cells from FH patients with LDLR mutations showed diminished activation post-immune challenge.

Conclusions:

• The LDLR pathway plays a significant role in supplying cholesterol essential for CD8+ T cell activation and function.
• Defects in LDLR-mediated cholesterol uptake impair T cell responses, highlighting a link between cholesterol metabolism and immunity.
• Findings in mouse models and FH patients underscore the clinical relevance of LDLR function in T cell-mediated immunity.