Integrating Experiment and Theory to Understand TCR-pMHC Dynamics

Abstract

The conformational dynamism of proteins is well established. Rather than having a single structure, proteins are more accurately described as a conformational ensemble that exists across a rugged energy landscape, where different conformational sub-states interconvert. The interaction between αβ T cell receptors (TCR) and cognate peptide-MHC (pMHC) is no exception, and is a dynamic process that involves substantial conformational change. This review focuses on technological advances that have begun to establish the role of conformational dynamics and dynamic allostery in TCR recognition of the pMHC and the early stages of signaling. We discuss how the marriage of molecular dynamics (MD) simulations with experimental techniques provides us with new ways to dissect and interpret the process of TCR ligation. Notably, application of simulation techniques lags behind other fields, but is predicted to make substantial contributions. Finally, we highlight integrated approaches that are being used to shed light on some of the key outstanding questions in the early events leading to TCR signaling.

Keywords: MHC; T cell activation; TCR; TCR recognition; conformational dynamics; immune synapse.

Figure 1

(A) Stylized view of the pMHC-TCR and core components required for T cell signaling. (B) Components of the pMHC-TCR complex for which structures have been determined in combination with one another. The complex depicts peptide-bound HLA-A*02 in complex with CD8 and the B7 TCR (derived by superimposing components of PDB ID's 1AKJ and 1BD2. (C) Portions of the CD3εγ (ectodomain; PDB ID 1SY6), CD3εδ (ectodomain; PDB 1XIW) and CD3ζζ (TM domains; PDB ID 2MAC) signaling components have been structurally determined, but not in complex with the TCR. Black lines represent regions of conformational flexibility. TCR α and β chain shown in dark and light blue, respectively. MHC class I heavy and light (β₂-microglobulin) chain shown in light and dark green, respectively. Peptide shown in red. CD8αα shown in orange.

Figure 2

Combinations of biophysical, structural, and computational techniques are a necessity to overcome the limitations of each individual technique and to rigorously understand the role of dynamics in TCR-pMHC function at the core of the immunological synapse. Biophysical techniques (yellow box), structural techniques (light orange box), computational techniques (dark orange box).

Figure 3

(A) Superposition of HuD-HLA peptide (red) (PDB ID 3PWL) and TCR-HuD-HLA peptide (brown) (PDB ID 3PWP) showing putative TCR binding-induced bond rotations. (B) Ensemble refinement show both these variants occur in the pMHC ensemble. MHC α-helices have been omitted.