The main goal of this project was to illuminate the problem of antigen discrimination by developing a physicochemical understanding of the interaction between T-cell receptors (TCRs) and peptide-loaded major histocompatibility complexes (pMHCs), and how this differs for pMHC with self and foreign peptides. The interaction between TCRs and pMHCs on contacting immune cells is the first, and arguably most important, step in initiating an adaptive immune response. It is also the interaction between TCR and pMHC that is the initial filter for our adaptive immune system to distinguish between our own cells and foreign pathogens, so called antigen discrimination. However, how this interaction differs between self and foreign pMHC, and how the binding kinetics is affected by TCR and pMHC being anchored to membranes, has been missing. I have in SELFOR been able to quantify this in physicochemical terms, with self being 2-3 orders of magnitude weaker than cognate antigen binding, but still detectable. This is important because it gives a first estimate of the binding window in which our immune system function, a binding window that is frequently missed when using directed antibodies for cell stimulation. I also discovered that small differences in binding affinity can still give rise to large differences in cell activation, stressing that it is not only the binding per see that gives rise to T-cell signalling but also the binding environment. In doing this I have had to develop a new means of measuring binding affinity in cell contacts as well as better understanding how auxiliary binding molecules can modulate the binding affinity of other ligand-receptor pairs by at least an order of magnitude, thus being able to significantly reduce the stimulating potency of an antigen. This again stresses the important of the binding environment. Finally, I have managed to study the CD4-pMHC-TCR interaction, showing that neither does CD4 influence TCR-pMHC binding nor does TCR influences CD4-pMHC binding. This is important in understanding the role of the co-receptor CD4, indicating that its role is to bring in activating kinases to already formed TCR-pMHC complexes instead of stabilizing them.
