Mechanisms and manipulation of force dependent behavior in T cell biology

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Summary TCR recognition of peptides bound and presented by MHC proteins underlies cellular immunity. TCR recognition of pMHC is most often viewed through the lens of traditional receptor-ligand theory, where cellular responses are presumed to be governed by solution binding affinities or kinetics. While this is often the case, work over the past several years has shown that complexities from mechanical forces exerted on membrane bound TCR and pMHC can profoundly influence T cell signaling. Of notable interest are catch bonds: force dependent enhancements of the lifetimes of TCR-pMHC complexes formed between interacting cells. Catch bonds can lead to large changes in signaling output and can greatly enhance T cell sensitivity. Demonstrating the importance of mechanical forces in tuning T cell responses, ligands that are recognized with strong affinity but fail to result in catch bonds yield altered or even no T cell signaling. Force-dependent behavior has been implicated in a wide range of T cell biological processes, including thymic education, responses to viral or tumor antigens, and viral escape. Although the importance of mechanical force in TCR recognition has been demonstrated, we have only a rudimentary understanding of how TCRs form catch or revert to slip bonds. We (PI Evavold) have had recent success in manipulating TCR catch bonds (published in Science this year) but this was achieved through screening libraries and without an understanding of mechanism. We thus lack predictive models for force dependent behavior in TCRs and in turn how this affects biology, which in turn impacts our ability to predict immunogenicity, assess the consequences of mutations, and hinders our ability to understand T cell specificity. Recently, however, we developed a comprehensive framework to identify, manipulate, and predict force dependent behavior in TCR-pMHC interactions. Unlike prior efforts, our framework directly addresses mechanism. Here, we will further develop, refine, and apply our framework. Our driving hypothesis is that viewing force dependent behavior through the lens of energy will provide the missing mechanistic detail of how and why catch bonds emerge in TCRs, allow their rational prediction and manipulation, and permit force considerations to be included in assessments of T cell recognition of antigen. Our three Aims are to 1) further develop our mechanistic framework for force dependent TCR behavior; 2) explain how changes to catch bonds emerge from natural variations in TCR interfaces and how catch bonds regulate T cell biology; and 3) Use rational catch bond engineering to better control viral infection in mice. Overall, the work in this proposal will illuminate the opaque mechanisms that underlie T cell mechanobiology, place catch bonds on a formal mechanistic footing, and provide the means to predict and productively manipulate TCR catch bonds and ultimately T cell biology.