Disruption of extracellular interactions impairs T cell receptor-CD3 complex stability and signaling

The alpha beta T cell antigen receptor (TCR), in complex with the CD3 delta epsilon, gamma epsilon, and zeta zeta 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 CD3 delta epsilon and CD3 gamma epsilon, subunits interact with the TCR via adjacent C alpha DE and C beta CC' loops, respectively. The TCR-CD3 delta epsilon interactions helped stabilize CD3 gamma epsilon 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.