A Cholesterol-Based Allostery Model of T Cell Receptor Phosphorylation

TY - JOUR

T1 - A Cholesterol-Based Allostery Model of T Cell Receptor Phosphorylation

AU - Swamy, Mahima

AU - Beck-Garcia, Katharina

AU - Beck-Garcia, Esmeralda

AU - Hartl, Frederike A.

AU - Morath, Anna

AU - Yousefi, O. Sascha

AU - Dopfer, Elaine Pashupati

AU - Molnár, Eszter

AU - Schulze, Anna K.

AU - Blanco, Raquel

AU - Borroto, Aldo

AU - Martín-Blanco, Nadia

AU - Alarcon, Balbino

AU - Höfer, Thomas

AU - Minguet, Susana

AU - Schamel, Wolfgang W A

PY - 2016/5/17

Y1 - 2016/5/17

N2 - Signaling through the T cell receptor (TCR) controls adaptive immune responses. Antigen binding to TCRαβ transmits signals through the plasma membrane to induce phosphorylation of the CD3 cytoplasmic tails by incompletely understood mechanisms. Here we show that cholesterol bound to the TCRβ transmembrane region keeps the TCR in a resting, inactive conformation that cannot be phosphorylated by active 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 peptide-MHC, which thus controlled TCR signaling. These data are explained by a model of reciprocal allosteric regulation of TCR phosphorylation by cholesterol and ligand binding. Our results provide both a molecular mechanism and a conceptual framework for how lipid-receptor interactions regulate signal transduction. The TCR can adopt an inactive, resting or an active, primed state. Schamel and colleagues show that the TCR is in equilibrium between these states. Peptide-MHC binding stabilizes the primed state that can be phosphorylated. Cholesterol binding stabilizes the resting state and thereby tunes the TCR activation threshold.

AB - Signaling through the T cell receptor (TCR) controls adaptive immune responses. Antigen binding to TCRαβ transmits signals through the plasma membrane to induce phosphorylation of the CD3 cytoplasmic tails by incompletely understood mechanisms. Here we show that cholesterol bound to the TCRβ transmembrane region keeps the TCR in a resting, inactive conformation that cannot be phosphorylated by active 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 peptide-MHC, which thus controlled TCR signaling. These data are explained by a model of reciprocal allosteric regulation of TCR phosphorylation by cholesterol and ligand binding. Our results provide both a molecular mechanism and a conceptual framework for how lipid-receptor interactions regulate signal transduction. The TCR can adopt an inactive, resting or an active, primed state. Schamel and colleagues show that the TCR is in equilibrium between these states. Peptide-MHC binding stabilizes the primed state that can be phosphorylated. Cholesterol binding stabilizes the resting state and thereby tunes the TCR activation threshold.

UR - https://www.scopus.com/pages/publications/84967142343

U2 - 10.1016/j.immuni.2016.04.011

DO - 10.1016/j.immuni.2016.04.011

M3 - Article

C2 - 27192576

AN - SCOPUS:84967142343

SN - 1074-7613

VL - 44

SP - 1091

EP - 1101

JO - Immunity

JF - Immunity

IS - 5

ER -