Catch Bonds at Cell-Cell Interfaces: Impact of Membrane Fluctuations

Abstract

Receptors on cell surfaces commonly engage membrane-presented ligands on other cells. An important example is the T cell receptor (TCR), which binds to ligands (pMHC) on antigen-presenting cells to stimulate T cell activation and the adaptive immune system. Recent experiments have shown that stimulatory TCR-pMHC bonds behave like catch bonds, with the average bond lifetime initially increasing with an increasing tensile force. Because T cells are initially stimulated by small numbers of TCR-pMHC complexes that experience a variety of forces, it is important to understand the behavior of small numbers of catch bonds in the presence of other surface molecules (SMs) and thermal fluctuations. To address this problem, we use computational methods to investigate the forces experienced by TCR-pMHC bonds at an intermembrane junction. We describe the energetics of the intermembrane junction with a modified Helfrich Hamiltonian and the SM concentration profile with an advection-diffusion PDE. We use a hybrid deterministic-stochastic algorithm to describe the dynamics, with the membrane locally equilibrating as the SM concentration profile evolves. Changes in membrane shape and SM organization lead to a time-dependent tension on the TCR-pMHC bonds, and fluctuations in the membrane shape lead to fluctuating forces experienced by the bonds. Using an experimentally parameterized model of catch bond kinetics, we construct bond rupture distributions for several different pMHC ligands. We show that the catch bond nature of stimulatory bonds enhances the survival probability in relation to conventional slip bonds in the presence of thermal fluctuations, and hence the catch bonds buffer against force fluctuations. Our computational framework provides a way to systematically study the binding of multiple bonds at generic cell-cell interfaces, and we discuss our results in terms of potential consequences for early T cell signaling.