Ca2+ regulates T cell receptor activation by neutralizing the charge of phospholipids (P1164)

Abstract

Abstract The inner-leaflet of the plasma membrane is enriched of anionic phospholipids, which interact with many positively charged proteins and regulate their function. The cytoplasmic domains of CD3ϵ and ζ chains in TCR-CD3 complex are enriched of basic residues and they interact with the inner-leaflet of the plasma membrane in quiescent T cells. Crucial tyrosine residues in ITAM insert into the hydrophobic core of the membrane, preventing the spontaneous tyrosine phosphorylation by Lck. An obvious follow-up question is what would dislodge ITAM from the membrane after TCR engagement. Ligation of TCR with agonist peptide-MHC can induce receptor clustering, which can disrupt ITAM-membrane binding and trigger the initial TCR phosphorylation and downstream signaling events including Ca2+ influx. As a divalent cation, Ca2+ directly binds to the phosphate group of phospholipids, which can disrupt the ionic interaction between CD3ϵ/ζ cytoplasmic domains and the plasma membrane and facilitate ITAM phosphorylation. This regulation can help the phosphorylation of bystander TCRs and amplify the weak initial ligand-induced TCR signaling. When compared with wild-type T cells, T cells deficient of CRAC channel have substantially lower TCR phosphorylation level after triggering. Our study thus demonstrates a positive feedback regulation of Ca2+ to TCR phosphorylation involving lipid manipulation, which helps explain the unique nature of T cell’s hypersensitivity to even a single antigen molecule.