Disruption of Extracellular Interactions Impairs T Cell Receptor-CD3 Complex Stability and Signaling

The αβ T cell antigen receptor (TCR), in complex with the CD3δε, γε, and ζζ signaling subunits, is the chief determinant for specific CD4⁺ and CD8⁺ T cell responses to self and foreign antigens. Although transmembrane domain charge interactions are critical for the assembly of the complex, the location of extracellular contacts between the TCR and CD3 subunits and their contributions to stability and signal transduction have not been defined. Here we used mutagenesis to demonstrate that the CD3δε and CD3γε subunits interact with the TCR via adjacent Cα DE and Cβ CC′ loops, respectively. The TCR-CD3δε interactions helped stabilize CD3γε within the complex and were important for normal T cell and thymocyte responses to TCR engagement. These data demonstrate that extracellular TCR-CD3 subunit interactions contribute to the structural integrity and function of this multisubunit receptor.