MHC binding affects the dynamics of different T-cell receptors in different ways.

Bernhard Knapp,Charlotte M Deane,Omer Dushek,P Anton Van Der Merwe

doi:10.1371/journal.pcbi.1007338

Abstract

T cells use their T-cell receptors (TCRs) to scan other cells for antigenic peptides presented by MHC molecules (pMHC). If a TCR encounters a pMHC, it can trigger a signalling pathway that could lead to the activation of the T cell and the initiation of an immune response. It is currently not clear how the binding of pMHC to the TCR initiates signalling within the T cell. One hypothesis is that conformational changes in the TCR lead to further downstream signalling. Here we investigate four different TCRs in their free state as well as in their pMHC bound state using large scale molecular simulations totalling 26 000 ns. We find that the dynamical features within TCRs differ significantly between unbound TCR and TCR/pMHC simulations. However, apart from expected results such as reduced solvent accessibility and flexibility of the interface residues, these features are not conserved among different TCR types. The presence of a pMHC alone is not sufficient to cause cross-TCR-conserved dynamical features within a TCR. Our results argue against models of TCR triggering involving conserved allosteric conformational changes.

Highlights

The interaction between T-cell receptors (TCRs) on the surface of T-cells and peptides bound by Major Histocompatibility Complexes (MHCs) on the surface of antigen presenting cells is one of the most important processes of the adaptive immune system [1]
MHC binding affects the dynamics of different T-cell receptors in different ways means that 98% of all randomly created group pairs have a smaller d value between them than the d value between TCRpMHC and TCR simulations
Our results show that the first is true for the LC13 and JM22 TCR while the A6 TCR shows a wider distribution and higher distance for TCR simulations (Fig 2)

Summary

Introduction

The interaction between T-cell receptors (TCRs) on the surface of T-cells and peptides bound by Major Histocompatibility Complexes (MHCs) on the surface of antigen presenting cells is one of the most important processes of the adaptive immune system [1]. The TCRs of T-cells bind to pMHCs with their six hypervariable Complementarity Determining Regions (CDRs) and thereby scan the pMHC (Fig 1A and 1B). Based on this interaction further downstream signalling cascades can be activated and an immune response can be elicited against a particular antigenic peptide. Conformational change models are of two types [2]: one group, based on the observation that pMHC binding will impose a mechanical pulling force on the TCR [3], proposes that this mechanical force somehow alters the conformation of TCR relative to the membrane and/or CD3 subunits [4,5,6]. Rossjohn and colleagues have reported a change in the AB loop of TCR Cα domain accompanying binding to agonist pMHC [7,12], but structural studies have failed to identify a conformation change conserved in all TCRs upon pMHC binding (reviewed in [2])

Methods

Results

Conclusion