Cholesterol metabolism in T cells in health and disease

Abstract

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.