Abstract
Dendritic cells (DCs) are the most effective professional antigen-presenting cell. They ferry antigen from the extremities to T cells and are essential for the initiation of an adaptive immune response. Despite interest in how DCs respond to chemical stimuli, there have been few attempts to model DC migration. In this paper, we simulate the motility of DCs by modeling the generation of forces by filopodia and a force balance on the cell. The direction of fliopodial extension is coupled to differential occupancy of cognate chemokine receptors across the cell. Our model simulates chemokinesis and chemotaxis in a variety of chemical and mechanical environments. Simulated DCs undergoing chemokinesis were measured to have a speed of 5.1 ± 0.07 μm·min-1 and a persistence time of 3.2 ± 0.46 min, consistent with experiment. Cells undergoing chemotaxis exhibited a stronger chemotactic response when exposed to lower average chemokine concentrations, also consistent with experiment. We predicted that when placed in two opposing gradients, cells will cluster in a line, which we call the “line of equistimulation;” this clustering has also been observed. We calculated the effect of varying gradient steepness on the line of equistimulation, with steeper gradients resulting in tighter clustering. Moreover, gradients are found to be most potent when cells are in a gradient of chemokine whose mean concentration is close to the binding of the Kd to the receptor, and least potent when the mean concentration is 0.1Kd. Comparing our simulations to experiment, we can give a quantitative measure of the strength of certain chemokines relative to others. Assigning the signal of CCL19 binding CCR7 a baseline strength of 1, we found CCL21 binding CCR7 had a strength of 0.28, and CXCL12 binding CXCR4 had a strength of 0.30. These differences emerge despite both chemokines having virtually the same Kd, suggesting a mechanism of signal amplification in DCs requiring further study.
Highlights
The adaptive immune system relies on antigen-presenting cells to bring antigen from peripheral tissues to secondary lymphoid organs (SLOs)
Dendritic cells use filopodia to pull themselves forward, and orient their filopodia based on signals received from chemokines
Dendritic cell migration cell motion based on a force balance, in which pulling from filopodia is counterbalanced by adhesive friction, and where the angular orientation of filopodia is based on the strength of chemotactic signal
Summary
The adaptive immune system relies on antigen-presenting cells to bring antigen from peripheral tissues to secondary lymphoid organs (SLOs). Immature DCs migrate through peripheral tissues until exposure to inflammatory cytokines or recognition of pathogenic antigen causes maturation [4]. DCs migrate quickly to SLOs and present antigen to T cells [5]. To fulfil their duties effectively, DCs must be able to both move quickly and exhibit directional motion in response to chemical signals. In mature DCs, the principal chemokine receptors are CXCR4 and CCR7 [6]. CXCR4 binds the chemokine CXCL12, while CCR7 can bind to either CCL19 and CCL21. CCL19 and CCL21 are both overexpressed in SLOs and are important for the recruitment of DCs [7], indicating that CCL19 and CCL21 guide DCs towards SLOs
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