Using DNA mechanotechnology to relate T cell biophysics to immunological function

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Kellner, Anna Victoria
Salaita, Khalid
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T cells survey the body for antigens by probing their environment through physical interactions. During these physical interactions, molecular-level forces transmitted through the T cell receptor (TCR) help discriminate antigenic tissue from self-tissue by prolonging TCR-antigen bonds and enhancing TCR signaling. This thesis describes the use of DNA mechanotechnology to help understand the role of these molecular-level forces in T cell function. First, we employed mechanotechnology to study the role of mechanics in PD1 receptor signaling. We found that the PD1 receptor is mechanically active, and that specific amino acid residues at the PD1-PDL2 interface are responsible for mechanical force transmission. Next, we used DNA mechanotechnology to study the role of plasma membrane cholesterol in TCR mechanics and signaling. We found that cholesterol depletion enhances TCR forces and triggering, and then hypothesized that this is due to cholesterol preventing TCR-cytoskeletal coupling. Finally, we used DNA mechanotechnology to investigate how the soluble microenvrionment tunes T cell function. We showed that the soluble microenvironment impacts cytoskeletal function and resulting T cell activation at the transcriptional and protein levels. We hypothesized that these changes were due to altered TCR mechanics and used DNA mechanotechnology to show that TCR forces are significantly altered by the soluble microenvironment. Importantly, we showed that TCR force modulation mirrored changes in the T cell functional response in both murine and human donor T cells. Our results suggest using “biomechanical biomarkers” to predict the outcomes of T cell-based immunotherapies prior to patient administration.
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