Cholesterol metabolism in T cells in health and disease
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Cholesterol is present in almost all eukaryotic cells and has many functions in health and disease. One of the cell types influenced by cholesterol are T cells. The aim of this review is to discuss the physiological and pathophysiological effects of cholesterol metabolism on T cell function and to provide an overview of the existing knowledge gaps. Cholesterol plays an important role in T cells by contributing to T cell activation and proliferation and determining T cell differentiation. Indeed, while differentiation of T helper (Th)1 cells, Th17 cells, γδT cells, cytotoxic T lymphocytes, and CD4+ memory T cells is stimulated by an active intracellular cholesterol biosynthesis, Th2 cells and CD8+ memory T cells require a suppressed cholesterol biosynthesis pathway. Differentiation of regulatory T (Treg) cells from naive T cells requires low cholesterol biosynthesis, while reactivation of Tregs is stimulated by an active flux of the biosynthesis pathway. Diseases in which cholesterol metabolism is disrupted display an altered T cell profile. This contributes to clinical symptoms in for example hypercholesterolemia, Tangier disease, and Smith-Lemli-Opitz syndrome patients. One of the biggest knowledge gaps on cholesterol metabolism in T cells is the relative contribution of cholesterol uptake, biosynthesis, efflux, and esterification on T cell function in health and disease. It also remains to be understood whether cholesterol biosynthesis and lipoprotein uptake are redundant mechanisms and in which way cholesterol esterification and uptake influence T cell function. Other outstanding questions include the mechanisms behind a reliance on cholesterol biosynthesis, the effects of statins on T cells, and the translation of results obtained in mice to humans. Unravelling the full picture of cholesterol metabolism in T cells will aid in the understanding of diseases with a disrupted T cell homeostasis, as well as to the development of efficient therapies.