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

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. The interaction between T-cells and other cells is one of the most important interactions in the human immune system. If T-cells are not triggered major parts of the immune system cannot be activated or are not working effectively. Despite many years of research the exact mechanism of how a T-cell is initially triggered is not clear. One hypothesis is that conformational changes within the T-cell receptor (TCR) can cause further downstream signalling within the T-cell. In this study we computationally investigate the dynamics of four different TCRs in their free and bound configuration. Our large scale simulations show that all four TCRs react to binding in different ways. In some TCRs mainly the areas close to the binding region are affected while in other TCRs areas further apart from the binding region are also affected. Our results argue against a conserved structural activation mechanism across different types of TCRs.