A cholesterol-based allostery model of T cell receptor phosphorylation

Immunity         online article

 Signaling through the T cell antigen receptor (TCR) initiates adaptive immune responses. Antigen binding to TCRab transmits signals through the plasma membrane to induce phosphorylation of the CD3 cytoplasmic tails by incompletely understood mechanisms. In recent BIOSS publications we have shown that the TCR can exist in two different conformations: an inactive, resting conformation and an active conformation. In this publication we show that cholesterol bound to the TCRb transmembrane region keeps the TCR in a resting, inactive conformation that cannot be phosphorylated by kinases. Only TCRs that spontaneously detached from cholesterol could switch to the active conformation (termed primed TCRs) and then be phosphorylated. Indeed, by modulating cholesterol binding genetically or enzymatically, we could switch the TCR between the resting and primed states. The active conformation was stabilized by binding to the ligand peptide-MHC, which thus controlled TCR signaling. These data are explained by a mathematical model of reciprocal allosteric regulation of TCR phosphorylation by cholesterol and ligand binding. This model was developed by the group of Thomas Höfer, Heidelberg, based on our data. Our results provide both a molecular mechanism and a conceptual framework for how lipid-receptor interactions regulate signal transduction.