Date of Award
Doctor of Philosophy
Steven M. Abel
Francisco Barrera, Eric T. Boder, Manolis Doxastakis
T cells orchestrate adaptive immunity, yet how they recognize and respond to small numbers of antigenic ligands remains an open question. T cells use surface receptors (TCRs) to engage membrane-presented ligands (pMHCs) on antigen-presenting cells (APCs). Recent experiments have illuminated the significance of mechanical forces, spatial organization, and dynamics of key proteins at cell-cell interfaces in immunology. For example, studies have shown T cells use actin-based microvillar protrusions to actively search APCs and stimulatory TCR-pMHC bonds exhibit catch-bond behavior, with an average bond lifetime that initially increases with increasing tensile force. It is unclear how mechanical forces at the cell-cell interface and force-dependent TCR-pMHC dissociation kinetics regulate antigen discrimination. Experimental observations raise the interesting question of whether T cells can exploit catch-bond behavior of stimulatory bonds as a physical mechanism in the search of rare antigenic ligands.In this dissertation, we employ computational methods to explore (i) the impact of TCR-pMHC bond formation on the spatial organization and shape of membranes at the cell-cell interface, (ii) the dynamics of TCR cluster formation, and (iii) the mechanical feedback between receptor-ligand binding and active force generation by scanning T-cell microvilli. We find the formation of individual TCR-pMHC bonds drives changes in the membrane organization and shape, leading to time-dependent forces on TCR-pMHC bonds. Using force-dependent lifetime data for TCRs bound to various ligands, we show that stimulatory catch bonds have a markedly enhanced average lifetime compared with non-stimulatory pMHCs. By varying the fraction and density of agonist pMHC on APCs, we demonstrate that stimulatory pMHC molecules play a central role in the formation of TCR clusters, and that TCR-pMHC clustering drives longer surface molecules away from regions of close apposition. Lastly, we find that a small number of catch bonds can initially immobilize T-cell microvilli, after which additional bonds accumulate and increase the cumulative receptor-engagement time. Thus, catch bonds can selectively slow and stabilize scanning microvilli, suggesting a physical mechanism that may contribute to antigen discrimination by T cells. Taken together, our results highlight the importance of force-dependent binding kinetics and cell mechanics for antigen discrimination at the T-cell-APC interface.
Pullen, Robert Henry III, "Computational modeling of cell mechanics and binding kinetics at T-cell interfaces. " PhD diss., University of Tennessee, 2019.