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    Michael E. Birnbaum.
    [alpha] [beta] T cells are central mediators of the adaptive immune system, tasked with cytotoxic functions and coordinating the B cell and innate immune responses. The T cell response relies upon the T cell receptor, rendered hugely diverse through V(D)J recombination, sampling peptides bound to MHC molecules to instill antigen specificity to the immune response. However, the number of possible peptide-MHC greatly outstrips the theoretical number of possible T cell receptors and surpasses the total number of T cells in any given organism by an even larger margin. The basis for how T cell receptors can be cross-reactive enough to ensure all possible antigens can be recognized while retaining enough specificity to avoid promiscuous T cell activation and autoimmunity has not been systematically examined. To address this, I harness a manmade system to generate large degrees of molecular diversity, yeast display (introduced in Chapter 1), to directly assay the degree and mechanism of T cell receptor cross reactivity. Upon exhaustively examining the peptide-MHC recognition repertoire for five T cell receptors (in Chapter 2), I find a surprisingly limited degree of diversity in the recognized sequences. Instead, cross-reactivity is accomplished via relatively conservative mutations in the T cell receptor contact epitope mated to a larger degree of mutation elsewhere in the presented peptide. Even the most seemingly diverse sequences recognized by any T cell receptor are recognized in structurally similar ways and can be connected via intermediate related sequences. I then leverage these close relationships to find naturally occurring peptide ligands for T cell receptors with a high rate of success. In Chapter 3, I further refine our system to find even lower affinity peptide-MHC ligands, relevant for T cell development, through evolving a piece of 'molecular velcro' that provides an additional point of attachment between the peptide and T cell receptor while preserving discrimination between binding and nonbinding peptides.
    Digital Access   2014