Abstract
Germinal centers (GCs) are complex dynamic structures that form within lymph nodes as an essential process in the humoral immune response. They represent a paradigm for studying the regulation of cell movement in the development of complex anatomical structures. We have developed a simulation of a modified cyclic re-entry model of GC dynamics which successfully employs chemotaxis to recapitulate the anatomy of the primary follicle and the development of a mature GC, including correctly structured mantle, dark and light zones. We then show that correct single cell movement dynamics (including persistent random walk and inter-zonal crossing) arise from this simulation as purely emergent properties. The major insight of our study is that chemotaxis can only achieve this when constrained by the known biological properties that cells are incompressible, exist in a densely packed environment, and must therefore compete for space. It is this interplay of chemotaxis and competition for limited space that generates all the complex and biologically accurate behaviors described here. Thus, from a single simple mechanism that is well documented in the biological literature, we can explain both higher level structure and single cell movement behaviors. To our knowledge this is the first GC model that is able to recapitulate both correctly detailed anatomy and single cell movement. This mechanism may have wide application for modeling other biological systems where cells undergo complex patterns of movement to produce defined anatomical structures with sharp tissue boundaries.
Highlights
Germinal centers (GCs) are anatomically discrete, dynamic sites in the follicles of lymphoid tissue (Figure 1A) that are an essential component of the adaptive immune response
PathSim2 (Pathogen Simulation 2) is an agent-based simulation that renders a small piece of tonsil lymphatic tissue, termed the Basic Tonsil Unit (BTU), consisting of a single follicle and all the relevant surrounding tissue necessary for its function (Figure 1, Video S1)
GC B-cell movement recapitulates in vivo dynamics We have demonstrated that a GC simulation capable of producing correct anatomy predicts, as purely emergent behavior, the single cell movement phenomenon of PRW
Summary
Germinal centers (GCs) are anatomically discrete, dynamic sites in the follicles of lymphoid tissue (Figure 1A) that are an essential component of the adaptive immune response (reviewed in [1,2]). The development of GCs requires the carefully choreographed movement of multiple cell types within an environment that is densely packed with cells (Figure S1C). This movement is driven by gradients of chemokines. The result is the production of a small number of antigen specific GC founder B-cells. These cells proliferate rapidly within the follicle for ,3 days (the initial expansion phase) [6,7], displacing the naive B-cells which form a characteristic structure around the GC termed the mantle zone (MZ) [6,7,8]. The MZ is discrete, the border with the GC is dynamic [9,10]; there is no physical barrier preventing naive B-cells from entering the GC
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