The CD3 ε subunit of the T cell receptor contains a basic-rich stretch important for multiple T cell functions (85.4)

Abstract

Abstract The TCR is a multimeric complex, consisting of a ligand-binding α/β heterodimer and four associated signaling chains (CD3γ, δ, ε, and ζ). The CD3 subunits each possess one or more copies of a signaling motif termed an ITAM, which is rapidly phosphorylated on tyrosine residues following TCR engagement. The cytoplasmic tails of CD3 ε and ζ also contain one or more clusters of basic amino acids. We report that these basic-rich stretches (BRS) can complex a subset of acidic phospholipids, including PI(4)P, PI(4,5)P2, and PI(3,4,5)P3. To determine how the BRS of CD3 ε contributes to T cell functions, we generated several CD3 ε constructs in which the positively charged residues of the BRS were eliminated. Analysis of these constructs in transfected cells revealed a role for the BRS in regulating both ITAM phosphorylation and TCR translocation to the immunological synapse. In transgenic mice, the introduction of modifications to the CD3 ε BRS resulted in a significant reduction in surface TCR expression and thymic cellularity. Furthermore, T cells from the BRS-mutant mice exhibited a diminished tyrosine phosphorylation of several signaling intermediates following TCR ligation. Based on these findings, we propose a model whereby electrostatic interactions between the BRS and phospholipids expressed on intracellular membranes regulate multiple T cell functions, including TCR expression and signaling.