Cytotoxic T cells represent an important line of defence in the vertebrate immune system to combat against intracellular abnormality such as viral and bacterial infections, as well as cellular transformation. In order to perform these functions effectively, cytotoxic T cells express αβ T cell receptors (αβ TCRs) on their cell surface, which allow them to specifically engage and differentiate self, altered self and foreign antigens on the surface of targeted cells. Intriguingly, such recognition

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... is genetically restricted to antigen presentation by the host Major Histocompatibility Complex class I (MHC-I) molecules, which typically bind to short peptide fragments between 8 to 10 amino acids in length. Longer antigens on the other hand, have also been shown to represent potential targets for cytotoxic T cells, although it is not fully understood how TCRs can accommodate these peptide-MHC-I landscapes. Contrasting TCR specificity, TCRs also simultaneously exhibit remarkable ability to cross-react onto different targets. This binding degeneracy forms an essential part of the protective immunity, and allows TCRs to effectively recognise a diverse range of antigens that is presented to the host. Understanding the dual specificity of TCR (specificity versus degeneracy) is important, as it not only plays central roles in protective immunity but also contributes to clinical manifestation such as graft rejection and graft-versus-host diseases during organ transplantation. Using X-ray crystallography and Surface Plasmon Resonance (SPR) approaches as main techniques, my thesis set out to explore the underlying basis of simultaneous TCR specificity and cross-reactivity in the context of lengthy antigens (>10 amino acids) derived from a ubiquitous human pathogen, Epstein-Barr Virus (EBV). These antigens, when bound to closely related Human Leukocyte Antigen (HLA, MHC in human) molecules, HLA-B*35:08 and HLA-B*35:01, exhibit a range of non-canonical structural features, either bulging away from the antigen-binding platform or [...]