RT Journal Article
SR Electronic
T1 Clustering of activated CD8 T cells around malaria-infected hepatocytes is rapid and is driven by antigen-specific T cells
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 508796
DO 10.1101/508796
A1 Reka K. Kelemen
A1 Ian A. Cockburn
A1 Vitaly V. Ganusov
YR 2018
UL http://biorxiv.org/content/early/2018/12/31/508796.abstract
AB 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 hours 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 hours, 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 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. Taken together, our analysis provides novel insights into and discriminates between alternative mechanisms driving the formation of clusters of antigen-specific CD8 T cells in the liver.