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.
Highlights
A eukaryotic plasma membrane is composed of a variety of lipids and sterols, such as cholesterol
The cholesterol-TCRβ interaction is dynamic, since only the non-ligand bound T cell antigen receptor (TCR) associated with cholesterol and the ligand-bound TCR did not (Swamy et al, 2016). These binding characteristics were recapitulated using purified TCRs and cholesterol-coupled beads (Beck-Garcia et al, 2013; Swamy et al, 2016) as only the resting TCR bound to these beads. This demonstrated that the dynamic cholesterol binding is a property of the TCRβ TM region and is not a consequence of altered membrane properties caused by ligand engagement
Concerning the mechanism of how cholesterol and sphingomyelin promote TCR nanoclustering, we suggested that cholesterol and sphingomyelin form a mini-raft-islet at the TCRβ TM region that is not favored to be in contact with the non-raft lipid domains that are around the TCR (Molnar et al, 2012; BeckGarcia et al, 2015)
Summary
A eukaryotic plasma membrane is composed of a variety of lipids and sterols, such as cholesterol. The most common composition of the plasma membrane is 20–50% phosphatidylcholine, 20–25% sphingomyelin, 30–50% cholesterol, 10% phosphatidylserine and 25% phosphatidylethanolamine (van Meer et al, 2008; Marquardt et al, 2015). One important sterol is cholesterol (Figure 1A), that is synthesized by the cells themselves and can be taken up from the environment. It determines membrane fluidity and permeability (Heerklotz and Tsamaloukas, 2006; Subczynski et al, 2017). Increase in membrane cholesterol increases lipid packing and stiffness causing decreased fluidity of lipid bilayers
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