Reticular network as the Lymph Nodes railroad system: T-cells migration modeling by the free energy minimization technique

One of the most important structural and functional elements of lymph nodes (LN) is the fibroblasts reticular network. Placed in vivo in the LN space, lymphocytes can move directionally, in fact, just along the reticular network, which act as a central immune highways. However, despite the multiple experimental studies, mechanisms regulating the lymphocytes motion are not fully understood. In this paper, we propose a modeling study of the basic mechanisms of the lymphocyte’s migration along the reticulum's linear part at the subcellular level. Model simulations were performed in order to test several possibilities of the stochastic T-cells motion along the reticular network driven by chemotaxis. The main goal of the work was to answer these questions using one of the microscopic modelling approaches and based on the free energy minimization technique, Cellular Potts Modeling. As result, wide range of possible hypotheses and various CPM Hamiltonians were tested. The spatial chemokine gradient is not a universal solution to the problem. The linear chemokine concentration distributed along the fiber does not solve the problem. Additionally, the production of chemokines by FRC fibers and their diffusion from the fiber into the lymph is not enough for a satisfactory solution as well. According to the proposed model, biologically relevant description of immune cells gliding along the reticular network can be achieved via a combination of linear gradient distributed along the fiber and a volume-distributed gradient without a normal "pressing" component. The volume-distributed chemokine's gradient becomes a successful solution in combination with the active type of cell motion and fibronectin fibers defined as spatial corridors, which in fact is in line with various experimental evidence.