Agent-based simulation of T-cell activation and proliferation within a lymph node.

Recent intravital microscopy experiments have revealed the complex behavior of T cells within lymph nodes. Modeling T-cell responses in lymph nodes now requires integration of cell trafficking and motility with the molecular processes involved in T-cell activation. We describe an agent-based model that allows such integration, in which T cells undertake a random walk through a three-dimensional representation of the lymph node paracortex, integrating signals from dendritic cells (DCs), and proliferating in response. The model accommodates simulation of a large number of T cells packed at realistic densities, and includes dynamic cell trafficking that allows the lymph nodes to swell and shrink as the immune response progresses. The results from the model, including the kinetics of cognate T-cell proliferation and release, and the changes in their avidity profile, are similar to those observed in vivo. We therefore propose that this modeling framework is capable of successfully simulating T-cell activation while also accounting for new spatiotemporal knowledge of how T cells and DCs interact. Although some of the parameters used to drive the model are not yet experimentally validated, the model is capable of testing the effects of alternative values for any parameter on the T-cell response. We intend to refine each aspect of the model in collaboration with both theoreticians and experimentalists.