Cholesterol Metabolism in T Cells

Abstract

Compartmentalization and spatial control of biochemical reactions is the foundation of cell-based life on earth. The lipid bilayer system employed by eukaryote cells not only keeps them separate from the environment but also provides a platform for key receptors to sense and interact with outside factors. Arguably one of the cell types most reliant on interactions of this kind, immune cells depend on their membrane to keep functioning properly. In this review, the influence of variation in cholesterol levels, a key component of lipid bilayer stability, on T cells will be discussed in detail. In comparison to other cells, T cells must be able to undergo rapid activation followed by proliferation. Furthermore, receptor colocalization is an important mechanism in this activation process. The impact of cholesterol availability on the processes of T cell proliferation and receptor sensitivity, as well as its potential for immunomodulation in disease treatment will be considered.

Keywords: T cell; cholesterol; disease; immunomodulation; metabolism.

Figure 1

Cholesterol and metabolite regulate T cell receptor clustering. Cholesterol can directly bind to the transmembrane domain of TCR-β chain to mediate TCR clustering on T cell surface, which can increase the avidity of TCR to foreign antigens and therefore augment TCR signaling. Meanwhile, cholesterol can keep TCR at an inactive conformation to avoid spontaneous signaling. Another safety control mechanism of TCR activity is the sequestration of TCR signaling motifs within the membrane bilayer via the ionic interactions between acidic phospholipids and polybasic regions in CD3 cytoplasmic domains. Cholesterol sulfate, a negatively charged cholesterol metabolite, however, can disrupt TCR clustering via the interference of cholesterol–TCR interaction. The underlying mechanism remains to be further illustrated.

Figure 2

Tools for modulating cholesterol metabolism of T cells. Summary of demonstrated tools for the modulation of T cell activity by targeting cholesterol metabolism in disease contexts. Tumor-infiltrating T cells are characteristic of hypoactivity, whereas auto-reactive T cells are of hyperactivity. Therefore, different strategies should be applied to modulate cholesterol metabolism in different disease contexts. Specific reagents as well as the observed effects on the cell are summarized. Avasimibe: inhibitor of acyl-coenzyme A: cholesterol acyltransferase; GW3865: agonist of liver X receptor; methyl-β-cyclodextrin: strong cholesterol binder that can deplete membrane cholesterol; atorvastatin: inhibitor of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase.