Random Migration and Signal Integration Promote Rapid and Robust T Cell Recruitment

Johannes Textor, Sarah E Henrickson, Judith N Mandl, Ulrich H von Andrian, Jürgen Westermann, Rob J de Boer and Joost B Beltman

PLOS Computational Biology, 2014, vol. 10, issue 8, 1-16

Abstract: To fight infections, rare T cells must quickly home to appropriate lymph nodes (LNs), and reliably localize the antigen (Ag) within them. The first challenge calls for rapid trafficking between LNs, whereas the second may require extensive search within each LN. Here we combine simulations and experimental data to investigate which features of random T cell migration within and between LNs allow meeting these two conflicting demands. Our model indicates that integrating signals from multiple random encounters with Ag-presenting cells permits reliable detection of even low-dose Ag, and predicts a kinetic feature of cognate T cell arrest in LNs that we confirm using intravital two-photon data. Furthermore, we obtain the most reliable retention if T cells transit through LNs stochastically, which may explain the long and widely distributed LN dwell times observed in vivo. Finally, we demonstrate that random migration, both between and within LNs, allows recruiting the majority of cognate precursors within a few days for various realistic infection scenarios. Thus, the combination of two-scale stochastic migration and signal integration is an efficient and robust strategy for T cell immune surveillance.Author Summary: Each of the immune system's T lymphocytes recognizes a highly specific molecular pattern, and only a very few T cells are capable of detecting any given infection. These rare cells are at first scattered throughout the body when a pathogen invades the host. To mount an immune response, they need to come together within lymphatic tissue near the infection site, and find cells that carry molecular fragments of the pathogen. Remarkably, experiments show that the immune system solves this needle-in-a-haystack problem in just a few days for various bacterial and viral infections. Aiming to understand how the immune system achieves this, we built a model that brings together classic and recent data on T cell migration. Our model explains how perpetual migration of T cells between and within lymphatic organs helps to find invading pathogens swiftly and reliably. Specifically, our results suggest that T cells can collect signals from activation-inducing cells for several hours, which allows for reliable detection of even low-profile infections. Thus, random T cell trafficking between and within lymphatic organs robustly protects against a broad range of pathogens, and comes close to an “optimal” surveillance strategy.

Date: 2014
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pcbi00:1003752

DOI: 10.1371/journal.pcbi.1003752

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