MD in TCRpMHC: chasing the structural trigger TCA

The interaction between major histocompatibility complex (MHC), presented peptide (p) and T-cell receptor (TCR) is essential in adaptive immunology. Although a lot of research has been done on these interaction processes, the structural trigger for T-cell activation is not known in detail. How is the signal routed from the interaction surface between pMHC and TCR into the T-cell? Which subtle structural mechanisms are responsible for eliciting an immune response or not? To investigate these questions we will systematically apply molecular dynamics (MD) simulations of up to 180 TCRpMHC complexes, for which immunogenicities are known from the literature. From the deformations in the TCR and MHC in reaction to agonistic and antagonistic peptides we will deduce general predictors for immunogenicity. These predictors will be formulated in mathematical terms via splines, principal component analysis and standard MD evaluation techniques, such as root mean square deviation (RMSD) or root mean square fluctuation (RMSF). In a sequential manner we will systematically simulate more and more TCRpMHC complexes while adjusting our predictors. Subsequently, we will apply those predictors to a second indepentend set of unpublished validation data provided by our clinical co-operation partners. The results of the validation set will be crucial to asses the quality of the predictors. After reliable predictors are established, they will help to explain immunological processes, observed by our co-operation partners, in a structural way. However, the long term aim is to provide a method which predicts the immunogenicity of an arbitrary TCRpMHC complex in silico using our predictors on the trajectories of MD simulations.

In this project we used computer simulations to show how special parts of the human immune system interact. There are certain cells which can be seen as the police of the human body (the so called T cells). Other cells present pieces of proteins on their surface to the T cells. On this basis the T cells have to decide whether the presented piece of protein is of danger to the human body or not. Although this process is known for quite a long time the detailed structural trigger for eliciting an immune response is not known. This is of special interest since if the human body is not able to react to a threat (e.g. a virus) this might be lethal for this person. On the other hand if the immune system reacts to harmless substances then autoimmune diseases or allergies can take place.Hence, it is of utmost importance to understand the mechanism of activating the immune response in detail. For this purpose we used computers to simulate the interaction of receptors on the surface of a T cell with other cells. In total we simulated 172 different situations in which the level of threat is known. On this basis we investigated the intrinsic movements of the cell receptors in reaction to these threats.This project was a very interdisciplinary approach at the border between information technology, mathematics, immunology, and cell biology which shed light on interaction processes which are not obtainable from the perspective of one single research field.