Direct Regulation of the T Cell Antigen Receptor's Activity by Cholesterol

Abstract

Biological membranes consist of hundreds of different lipids that together with the embedded transmembrane (TM) proteins organize themselves into small nanodomains. In addition to this function of lipids, TM regions of proteins bind to lipids in a very specific manner, but the function of these TM region-lipid interactions is mostly unknown. In this review, we focus on the role of plasma membrane cholesterol, which directly binds to the αβ T cell antigen receptor (TCR), and has at least two opposing functions in αβ TCR activation. On the one hand, cholesterol binding to the TM domain of the TCRβ subunit keeps the TCR in an inactive, non-signaling conformation by stabilizing this conformation. This assures that the αβ T cell remains quiescent in the absence of antigenic peptide-MHC (the TCR's ligand) and decreases the sensitivity of the T cell toward stimulation. On the other hand, cholesterol binding to TCRβ leads to an increased formation of TCR nanoclusters, increasing the avidity of the TCRs toward the antigen, thus increasing the sensitivity of the αβ T cell. In mouse models, pharmacological increase of the cholesterol concentration in T cells caused an increase in TCR clustering, and thereby enhanced anti-tumor responses. In contrast, the γδ TCR does not bind to cholesterol and might be regulated in a different manner. The goal of this review is to put these seemingly controversial findings on the impact of cholesterol on the αβ TCR into perspective.

Keywords: T cell; TCR; allostery; cholesterol; lipid; nanocluster; signaling.

Figure 1

Cholesterol and the TCR. (A) Structure of cholesterol and the cholesterol sphingomyelin pair. (B) Schematic of the resting, inactive TCR, in which the cytoplasmic signaling motifs of the CD3 and ζ subunits are not accessible (right), and of the active TCR with the pMHC ligand bound (left), in which the motifs are exposed. The ITAM, BRS, PRS, and RK motifs are indicated.

Figure 2

Cholesterol's function of regulating the allosteric switch of the TCR. The TCR can switch spontaneously between the inactive and active state (allosteric switch). Cholesterol binds to the TCRβ subunit only in the inactive TCR, thus shifting the equilibrium to the left side. The pMHC ligand binds to the TCRαβ subunits only in the active TCR, thus shifting the equilibrium to the right side. Only in the active state the TCR can be phosphorylated transmitting the signal of pMHC-binding downstream.

Figure 3

Cholesterol's function of regulating nanoclustering of the TCR. With low levels of cholesterol and sphingomyelin TCRs are expressed as monomers on the cell surface (left)—as it is the case in naïve T cells. With increasing concentrations of cholesterol and sphingomyelin, these lipids bind to the TCR and cause TCR nanoclustering—as it is the case in activated and memory T cells.