Striking streaks · Invariant Natural Killer T-cells in atherogenesis

Invariant Natural Killer T-cells in atherogenesis

Many survivors of childhood chronic disease struggle with early atherosclerosis later in life. As a physician-scientist I am inspired by their lifelong fight, and my research focuses on the etiology, diagnosis, and prevention of early atherosclerosis in children at risk. During the MSCA Fellowship I studied one of the cellular players involved in atherogenesis, so-called invariant Natural Killer T (iNKT) cells. iNKT cells are unique immune cells for their restriction to lipid antigens rather than peptide antigens, which underlies their pivotal role in lipid-driven disorders such as atherosclerosis. The exact role of iNKT cells in atherogenesis however remains elusive, because the origin of the lipid antigens in atherosclerosis is currently unknown. Importantly, more insight in the role of iNKT cells in atherogenesis may enable harnessing of iNKT cells for cardiovascular protection in the future. During my MSCA Fellowship at the cardiovascular immunology laboratory of Professor Monaco at the Kennedy Institute of the University of Oxford, I focused on three objectives. First, I studied whether lipid antigens are contained in the circulating lipoprotein fraction, which plays a critical role in atherosclerosis. Next, I studied the impact of lipoprotein-associated lipid antigens on iNKT cell function. Finally, I explored whether manipulation of lipoprotein metabolism impacts the function of iNKT cells. Since circulating lipoproteins routinely contain lipids that are structurally similar to lipid antigens, I hypothesized that circulating lipoproteins would also contain lipid antigens for iNKT cells. I developed CD1d-sortagging as a novel and innovative approach for lipid antigen identification. CD1d-sortagging employs bacterial sortase enzymes for site-specific cleavage and biotin labeling of CD1d-lipid antigen complexes, followed by isolation and potentially identification of the lipid antigens. Using CD1d-sortagging and state-of-the-art microscopy techniques, I have been able to show that circulating lipoproteins can indeed contain lipid antigens for iNKT cell function. Furthermore, I discovered that the containment of lipid antigens in lipoproteins affects iNKT cell function. Finally, I showed that manipulation of lipoprotein metabolism impacts the delivery of lipid antigens to antigen presenting cells, and thereby the function of iNKT cells. In conclusion, the MSCA Fellowship project showed that lipoproteins are not only involved in plaque development as lipid deposits, but also play a role in the activation of iNKT cells.

Data: CORDIS, © European Union