The adaptive immune system is a rich and complex field of study, with incremental improvements in our understanding of the fundamental machinations of some of its core components providing translation developments such as improved vaccines against infectious disease, drugs that can limit the severity of allergic reactions, and immunotherapies for treatment of a wide range of cancers. At the level of basic science, specific subsets of the adaptive immune response each have key questions spanning topics ranging from evolution and cellular communication to non-equilibrium thermodynamics and statistical mechanics. Indeed, investigations aimed at interrogating adaptive immunity require increasingly interdisciplinary approaches. In this thesis, we outline research at the interface of molecular immunology and computational biophysics, focusing on non-canonical immunological niches that break from the classical descriptions of adaptive immunity. We first investigate the role of broad reactivity to diverse molecular species in antibodies, molecules that have long been suggested to be highly specific binders to single molecular targets. Through a novel bioinformatic approach, we are able to identify the critical molecular features that confer this broad reactivity, referred to as polyreactivity, in antibodies. Next, we turn our attention to uncovering an elusive activation mechanism of a specific subset of T cells, Vγ9Vδ2 T cells. Unlike the canonical αβ T cells, these Vγ9Vδ2 T cells are activated independent of antigenic peptides or major histocompatibility complexes. Using a combination of computational approaches, we reassess a prominent model in the field and propose a new, clustering based model for activation. While these interdisciplinary approaches provide fundamental insights into complex biological phenomena, they also represent a powerful analytical framework for broader inquiries into molecular processes in immunology. Collectively, the approaches and computer code outlined herein should serve as a template to improve the pace of scientific discovery in this space.




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