(590f) Catch Bonds at T Cell Interfaces

An open problem in immunology is how T cells, which orchestrate the adaptive immune response, reliably distinguish and respond to small numbers of antigenic ligands in a sea of non-stimulatory ligands. T cell activation is thought to depend largely upon the binding kinetics between the T cell receptor (TCR) and membrane-presented ligands (pMHC) on other cells, but binding kinetics in situ are influenced by physical properties of the cell-cell interface and are difficult to characterize experimentally. Recently, experiments have shown that TCR-pMHC bonds experience a variety of forces at the cell-cell interface and that stimulatory bonds behave as catch bonds, with an average bond lifetime that initially increases with an increasing tensile force. Because T cells are initially stimulated by small numbers of TCR-pMHC complexes, it is important to understand how bond formation drives dynamic changes in membrane organization, how these changes affect forces experienced by the bonds, and ultimately how these forces affect bond lifetimes.

Here, we use computational methods to characterize time-dependent forces on TCR-pMHC bonds in response to changes in the membrane shape and the organization of other surface molecules. We then determine the distributions of bond lifetimes using recent force-dependent lifetime data for T cell receptors bound to various ligands. Strong agonists, which exhibit catch bond behavior, are markedly more likely to remain intact than an antagonist whose average lifetime decreases with increasing force. Thermal fluctuations of the membrane shape enhance the decay of the average force on a bond, but also lead to fluctuations of the force. These fluctuations promote bond rupture, but the effect is buffered by catch bonds. When more than one bond is present, the bonds experience reduced average forces that depend on their relative positions, leading to changes in bond lifetimes. Our results highlight the importance of force-dependent binding kinetics when bonds experience time-dependent and fluctuating forces. This is suggestive from a mechanistic standpoint, as force-dependent regulation of TCR-pMHC binding times provides a physical mechanism that could help T cells discriminate between self and foreign ligands.