Clustering of CD8 T cells around malaria-infected hepatocytes is rapid and is driven by antigen-specific T cells

Abstract

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. In mice, vaccine-induced CD8 T cells are capable of locating and eliminating all liver stages in 48 hours, thus preventing the blood-stage disease. 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 Py-infected cells, 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 T cells) can accurately explain the available data. Second, while both Py-specific CD8 T cells and T cells of irrelevant specificity (non-specific T cells) are attracted to the clusters, we found no evidence that non-specific 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 T cells, thus illustrating high efficiency of T cells in locating their targets in complex peripheral organs such as the liver. Our analysis thus clarifies details of the formation of clusters of antigen-specific CD8 T cells in the liver.