PhD work by Angela Markovska at UMC Utrecht shows that LDL-receptor mediated lipoprotein uptake influences T cell function. In addition, her research highlights an immune-modulating role for PCSK9 (a protein that regulates cholesterol homeostasis), uncovers the capacity of lipoproteins to deliver antigens, and demonstrates that enhancing antigen presentation on tumor cells can strengthen T cell activity. Together, these findings advance our understanding of T cell biology and offers potential new strategies for treating autoimmune disorders, cancer and metabolic diseases.
T cells are key immune cells that protect the body against infections and cancer. To perform this role, they must rapidly switch from a resting state to an active state when they encounter a threat. This process requires major changes in cellular metabolism, which is the way how cells obtain and use nutrients and energy. While metabolism is known to strongly influence T cell function, the role of lipid metabolism and lipoprotein uptake in T cells remains incompletely understood.
Angela Markovska receives her PhD certificate
The PhD thesis of Angela Markovska (Center for Translational Immunology, UMC Utrecht) investigated how lipoproteins (particles that transport fats such as cholesterol in the bloodstream) affect T cell responses. Low-density lipoprotein (LDL) delivers cholesterol to cells through the LDL receptor (LDLR), a pathway that is present in many cell types, including immune cells. However, its importance for T cell biology has not been well defined.
The work of Angela first demonstrated that circulating lipoproteins can function as carriers of lipid antigens. These lipoproteins deliver lipid antigens to invariant natural killer T cells, leading to their activation. This finding reveals a previously underappreciated immunological role for lipoproteins in antigen transport.
Further studies showed that LDLR-mediated lipoprotein uptake plays an important role in conventional T cell function. Using immune cells from patients with homozygous familial hypercholesterolemia (a genetic condition that disrupts LDLR function) the research by Angela Markovska demonstrated that impaired lipoprotein uptake alters T cell behavior. Moreover, in CD4+ T cells, LDLR-dependent lipid uptake supported activation, proliferation, and differentiation, particularly promoting the development of interleukin-10-producing immunoregulatory T cells.
In CD8+ T cells, regulation of LDLR expression also strongly influences immune function. The protein PCSK9 appeared to reduce LDL receptor levels on T cells, which impaired their activation and cytotoxic activity. Importantly, pharmacological inhibition of PCSK9 restored the ability of CD8+ T cells to kill target cells. These findings suggest that cholesterol-lowering drugs targeting PCSK9 could potentially be repurposed to enhance cancer immunotherapy.
Additional work identified strategies to improve tumor recognition by increasing MHC class I expression on tumor cells. This makes tumor cells more visible to CD8+ T cells and strengthens immune-mediated tumor destruction.
Together, these results demonstrate that lipoprotein uptake and lipid metabolism are important regulators of T cell activation and function. The findings reveal new connections between lipid metabolism and immune regulation and suggest that targeting metabolic pathways may offer new opportunities to improve treatments for inflammatory diseases and cancer.
Angela Markovska, PhD (1996, Skopje, North Macedonia) defended her PhD thesis on March 3, 2026, at Utrecht University. The title of her thesis was “Where lipoproteins meet T cells – LDL receptor in the growing landscape of immune modulation.” Supervisor was Marianne Boes, PhD (Center for Translational Immunology, UMC Utrecht) and co-supervisor was Henk Schipper, MD PhD (Department of Pediatric Cardiology, Erasmus MC, Rotterdam). In April 2025, Angela started as a postdoctoral researcher at the Department of Biomolecular Health Sciences at Utrecht University.
