Where lipoproteins meet T cells: LDL receptor in the growing landscape of immune modulation

T cells are highly adaptable immune cells that play a central role in host defense against infections, malignancies, and other threats. For effective immune responses, T cells must rapidly switch from a resting state to an active, energy-demanding state after recognizing antigen, and subsequently return to a quiescent state once the threat has been cleared. Tight regulation of this dynamic process is essential for immune homeostasis, as uncontrolled or prolonged T cell activation can result in chronic inflammation, tissue damage, or the development of autoimmune disease. T cell function is closely linked to intracellular metabolism. Nutrient uptake and energy metabolism are now recognized as key determinants of T cell activation, differentiation, and function. Within this context, the role of lipid metabolism, and specifically the use of lipoproteins by T cells, remains incompletely understood. Lipoproteins are the primary transporters for lipids such as cholesterol and triglycerides in the circulation. Low-density lipoprotein (LDL) delivers cholesterol to peripheral tissues, where it is essential for membrane synthesis, hormone production, and cellular growth. Cellular LDL uptake is largely mediated by the LDL receptor (LDLR), which is expressed by many cell types, including immune cells. Despite the fundamental importance of this pathway, its role in T cell biology has remained poorly characterized.

This thesis investigates whether T cell responses can be modulated through manipulation of lipoprotein uptake and metabolism. Chapter 2 establishes a conceptual framework by introducing the field of immunometabolism, outlining how metabolic pathways and nutrient availability shape immune cell behavior, and highlighting their relevance in chronic inflammatory diseases such as atherosclerosis and cancer. Chapter 3 uncovers an immunological role for lipoproteins as carriers of lipid antigens, showing that circulating lipoproteins can transport lipid antigens to invariant natural killer T (iNKT) cells and induce their activation. Chapters 4 and 5 further delineate the role of LDLR-dependent lipoprotein uptake in CD4+ and CD8+ T cell subsets. Using cells derived from patients with homozygous familial hypercholesterolemia (hoFH), with mutations in the LDLR, this work demonstrates the importance of LDLR-mediated lipoprotein uptake in T cell function. LDLR-mediated uptake shaped CD4+ T cell activation, proliferation, and differentiation, particularly promoting the development of IL-10-producing immunoregulatory CD4+ T cells. In CD8+ T cells, PCSK9-mediated downregulation of LDLR impaired activation and effector function, whereas pharmacological inhibition of PCSK9 restored cytotoxic capacity, revealing opportunities to repurpose cholesterol-lowering therapies to enhance cancer immunotherapy. Chapter 6 explores strategies to improve tumor antigen presentation by increasing MHC class I expression, thereby enhancing CD8+ T cell-mediated tumor recognition. Finally, Chapter 7 emphasizes the metabolic flexibility of T cells, underscoring the therapeutic potential and complexity of targeting interconnected metabolic networks to modulate immune responses.

Together, these findings establish lipoprotein metabolism as a key modulator of T cell immunity and underscore metabolic pathways as promising, though complex, targets for therapeutic intervention.