Lymph node topology dictates T cell migration behavior

Abstract

Adaptive immunity is initiated by T cell recognition of foreign peptides presented on dendritic cells (DCs) by major histocompatibility molecules. These interactions take place in secondary lymphoid tissues, such as lymph nodes (LNs) and spleen, and hence the anatomical structure of these tissues plays a crucial role in the development of immune responses. Two-photon microscopy (2PM) imaging in LNs suggests that T cells walk in a consistent direction for several minutes, pause briefly with a regular period, and then take off in a new, random direction. Here, we construct a spatially explicit model of T cell and DC migration in LNs and show that all dynamical properties of T cells could be a consequence of the densely packed LN environment. By means of 2PM experiments, we confirm that the large velocity fluctuations of T cells are indeed environmentally determined rather than resulting from an intrinsic motility program. Our simulations further predict that T cells self-organize into microscopically small, highly dynamic streams. We present experimental evidence for the presence of such turbulent streams in LNs. Finally, the model allows us to estimate the scanning rates of DCs (2,000 different T cells per hour) and T cells (100 different DCs per hour).

Characterizing T Cell Movement within Lymph Nodes in the Absence of Antigen

“…Another detailed model for the movement of T cells and dendritic cells in lymph nodes was proposed by Beltman et al (25). They use it to investigate the possibility that T cells and dendritic cells owe the characteristics of their motility patterns (i.e., runand-pause random walk) to the anatomical structure of lymph nodes.…”

Modeling Morphogenesisin silicoandin vitro: Towards Quantitative, Predictive, Cell-based Modeling

“…Indeed, in vitro vasculogenesis may require endothelial cell persistence [2,48,15]. A number of authors have proposed CPM extensions for making cells directionally persistent [6,5,26]. These methods assign a target direction or target velocity to the cell and favor motility in the target direction.…”

“…These methods assign a target direction or target velocity to the cell and favor motility in the target direction. The target direction of motion can be pre-assigned [6,26] or derived from the cells' instantaneous velocity [5]. In both methods the target direction becomes a running mean over the cells' past movements.…”

“…In this way the cells' movements depend both on its past movement (persistence) and on local variables, including chemoattractants or the interaction with neighboring cells. Cell motility and cell persistence parameters are easily derived from cell tracking experiments (see, e.g., [6]) but in more advanced methods we could make the persistence parameters a function of local signals. For example, Reinhart-King [40] and coworkers observed attractive and repulsive pairwise interactions between endothelial cells, depending on Matrigel compliance.…”

Reaction-Diffusion Modelling of Interferon Distribution in Secondary Lymphoid Organs

“…The focus should be made on the development of hybrid multiphysics models which integrate the spatial migration of cells and soluble substances in the lymphoid system with the real 3D geometry of immune responses microanatomy in SLO, calibrated using high-resolution fluorescence microscopy data. Although, there is a growing interest to explore the spatial complexities of the immune processes using mathematical models [2,3,4,14,18,25], the real 3D geometry of the SLO remains to be properly considered. Further studies of the similar to the presented here and recent imaging technology-driven computational developments [15] should provide a proper basis for a transition in the current modelling paradigm of mathematical immunology from a phenomenological, spatially degenerate approach to a multiphysics-based high-resolution description of immune responses in physiological environment of the organized lymphoid tissues [30].…”