Chemorepulsion and Chemoattraction of Malignant T cells in CCL19 Gradients of Various Strengths

Chemokine (C–C motif) ligand 19 (CCL19) is a protein that T cells can sense and follow. Experiments have shown that the behavior of single malignant T cells varies depending on the steepness of the CCL19 gradient: steep gradients repulse cells, intermediate gradients attract them, and shallow gradients appear to cause random motion. How can one chemical cue produce such radically different responses depending on the gradient strength? We develop a computational model that unites the variety of behaviors exhibited by malignant T cells exposed to different CCL19 gradients. We use Monte Carlo simulations to model the stochastic binding and unbinding of CCL19 to receptors, as well as the desensitization, internalization, and recycling of receptors. We propose that the sensed concentrations of CCL19 regulate these processes. Our model reproduces the switch in migration direction. We compare our simulations to measurements of cell trajectories and the forward motion index at different gradient strengths as well as different overall concentrations of CCL19.