Pathan-Chhatbar Salma, Drechsler Carina, Richter Kirsten, Morath Anna, Wu Wei, OuYang Bo, Xu Chenqi, Schamel Wolfgang W
Centre for Biological Signalling Studies and Centre for Integrative Biological Signalling Studies, University Freiburg, Freiburg, Germany.
Department of Immunology, Faculty of Biology, University of Freiburg, Freiburg, Germany.
Front Cell Dev Biol. 2021 Jan 8;8:615996. doi: 10.3389/fcell.2020.615996. eCollection 2020.
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.
生物膜由数百种不同的脂质组成，这些脂质与嵌入的跨膜（TM）蛋白一起自组装成小的纳米结构域。除了脂质的这种功能外，蛋白质的TM区域以非常特定的方式与脂质结合，但其功能大多未知。在本综述中，我们重点关注质膜胆固醇的作用，它直接与αβ T细胞抗原受体（TCR）结合，并在αβ TCR激活中至少具有两种相反的功能。一方面，胆固醇与TCRβ亚基的TM结构域结合，通过稳定该构象使TCR保持无活性的非信号传导构象。这确保了αβ T细胞在没有抗原肽 - MHC（TCR的配体）的情况下保持静止，并降低了T细胞对刺激的敏感性。另一方面，胆固醇与TCRβ的结合导致TCR纳米簇的形成增加，从而增加了TCR对抗原的亲和力，进而增加了αβ T细胞的敏感性。在小鼠模型中，T细胞中胆固醇浓度的药理学增加导致TCR聚集增加，从而增强了抗肿瘤反应。相比之下，γδ TCR不与胆固醇结合，可能以不同的方式受到调节。本综述的目的是正确看待这些关于胆固醇对αβ TCR影响的看似矛盾的发现。
