Computer simulations of mechanical forces and spatial organization at the immunological synapse

The binding of immune receptors with their cognate ligands is a pivotal interaction at the forefront of the body's defense mechanisms against pathogens. The process begins with the recognition and engagement of specific ligands by transmembrane receptor proteins on the surface of immune cells. When a compatible ligand binds to its corresponding receptor, a cascade of molecular events is triggered, initiating a series of organizational changes that result in the formation of a specialized region of membrane known as the immunological synapse. This synapse serves as a locus for enabling coordination of immune cell activation, signaling, and effector functions through the interplay of biochemical signaling, cytoskeletal rearrangements, and membrane dynamics.

In addition to the organizational information and membrane shape, the immunological synapse features intricate patterns of mechanical force. The function of these observed forces remains an open question. Due to the restrictive spatial and temporal scales of processes at the immune synapse, opportunities arise to employ a variety of computational methods. In this dissertation, we set out to apply computer models to gain insight into the function of forces and spatial organization in the immune synapse.

Specifically, we describe a suite of research projects concerning the T cell synapse and macrophage phagocytic synapse. We first explore how force modulates the organizational structure of macrophages undergoing phagocytosis, demonstrating that forces originating from a pathogen could have a negative effect on the immune response. We then turn to the T cell immune synapse to study the patterns of force utilized by T cells during lytic granule release. Here, we identify a range of force patterns associated with optimum performance in target cell disruption. We then consider the impact of receptor clustering on the binding behavior. Finally, model the bistability of a multisite phosphorylation cascade in two compartments while varying the rate of particle exchange between the compartments. This cell signaling motif is key to T cell signaling. Collectively, these results contribute to expanding the understanding of biological mechanisms that play vital roles in the immune response. These projects represent exciting and previously underdeveloped lines of inquiry.