Evidence for a pivot upon TCR engagement (IRM7P.700)

Abstract

Abstract The T cell receptor (TCR)-CD3 complex is the chief determinant for T cell development, activation, differentiation and the execution of effector functions. The TCR module (TCRα+TCRβ) relays highly specific information about antigenic peptides embedded within major histocompatibility complex molecules (pMHC) to the intracellular signaling domains of the associated CD3γε, CD3δε, and CD3ζζ signaling modules to initiate intracellular signaling. It is unclear how mechanical information is transferred from the TCR-pMHC interface, across the plasma membrane, and on to the intracellular signaling domains of the CD3 subunits. The complexity of this molecular machinery, and the lack of obvious parallels with other receptor systems, has hindered progress in resolving these issues. We tested the hypothesis that the juxtamembrane regions of the CD3 signaling subunits are held in a spatial relationship that keeps the complex ‘off’ until TCR engagement triggers a change in this spatial relationship that converts the complex to an ‘on’ conformation. This would be akin to cytokine receptors, receptor tyrosine kinases, and even integrins. Our data indicate that unengaged TCRs enforce a divaricated conformation of the cytosolic juxtamembrane regions of key TCR-CD3 complex subunits at steady state. We interpret this to represent an off conformation. TCR engagement then triggers the intra-complex apposition of these regions into what we interpret to represent an on conformation.