Clustering of Activated CD8 T Cells Around Malaria-Infected Hepatocytes Is Rapid and Is Driven by Antigen-Specific Cells.

Reka K Kelemen,Ian A Cockburn,Harshana Rajakaruna,Vitaly V Ganusov

doi:10.3389/fimmu.2019.02153

Abstract

Malaria, a disease caused by parasites of the Plasmodium genus, begins when Plasmodium-infected mosquitoes inject malaria sporozoites while searching for blood. Sporozoites migrate from the skin via blood to the liver, infect hepatocytes, and form liver stages which in mice 48 h later escape into blood and cause clinical malaria. Vaccine-induced activated or memory CD8 T cells are capable of locating and eliminating all liver stages in 48 h, thus preventing the blood-stage disease. However, the rules of how CD8 T cells are able to locate all liver stages within a relatively short time period remains poorly understood. We recently reported formation of clusters consisting of variable numbers of activated CD8 T cells around Plasmodium yoelii (Py)-infected hepatocytes. Using a combination of experimental data and mathematical models we now provide additional insights into mechanisms of formation of these clusters. First, we show that a model in which cluster formation is driven exclusively by T-cell-extrinsic factors, such as variability in “attractiveness” of different liver stages, cannot explain distribution of cluster sizes in different experimental conditions. In contrast, the model in which cluster formation is driven by the positive feedback loop (i.e., larger clusters attract more CD8 T cells) can accurately explain the available data. Second, while both Py-specific CD8 T cells and T cells of irrelevant specificity (non-specific CD8 T cells) are attracted to the clusters, we found no evidence that non-specific CD8 T cells play a role in cluster formation. Third and finally, mathematical modeling suggested that formation of clusters occurs rapidly, within few hours after adoptive transfer of CD8 T cells, thus illustrating high efficiency of CD8 T cells in locating their targets in complex peripheral organs, such as the liver. Taken together, our analysis provides novel insights into and attempts to discriminate between alternative mechanisms driving the formation of clusters of antigen-specific CD8 T cells in the liver.

Highlights

Malaria is a life-threatening disease that is a result of red blood cell destruction by eukaryotic parasites of the Plasmodium genus
This may arise because individual parasites may induce different degrees of inflammation as they migrate from the blood into the liver parenchyma, or some parasites may infect hepatocytes which are located in liver parts with a larger blood flow, increasing the chance of T cells to locate such parasites [35, 49,50,51]
Application of mathematical models to data on distribution of the number of Plasmodium yoelii (Py)-specific CD8 T cells around randomly chosen parasites suggested that formation of the clusters is not a random process; the model in which activated T cells of different specificities are attracted at a rate proportional to the number of Py-specific T cells already present near the parasite, described the data with best quality [29]

Summary

Introduction

Malaria is a life-threatening disease that is a result of red blood cell (erythrocyte) destruction by eukaryotic parasites of the Plasmodium genus. Studies have estimated that the initial number of sporozoites entering the host is as low as 10–50 [5, 6], of which only a fraction succeed to migrate to the liver to start an infection of hepatocytes by forming liver stages [7,8,9]. This liver stage of infection lasts for ∼6.5 days in humans and about 2 days in mice [10,11,12,13]. Specific mechanisms by which CD8 T cells achieve such an efficiency remain poorly defined

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Conclusion