A new method shows that a minority of liver-localized CD8 T cells display hard-to-detect attraction to Plasmodium-infected hepatocytes

Malaria is a disease caused by Plasmodium parasites, resulting in over 200 million infections and 400,000 deaths every year. A critical step of malaria infection is when mosquito-injected sporozoites travel to the liver and form liver stages. Malaria vaccine candidates tested in mice induce large numbers of malaria-specific CD8 T cells that are able to eliminate all liver stages. However, how CD8 T cells find infection sites is not well understood. We generated data using intravital microscopy in mice where T cell movement in the liver was recorded in different settings. To detect attraction of T cells to an infection site, we developed a metric based on the Von Mises-Fisher distribution, which detects attraction more powerfully than previous metrics. Our results suggested that the majority (70-95%) of malaria-specific CD8 T cells and non-specific T cells did not display attraction when the parasite was not found, but some T cells displayed strong attraction when T cells clustered near the parasite. We found that speeds and turning angles correlated with attraction, suggesting that understanding what determines the speed of T cell movement in tissues may improve T cell vaccine efficacy. Stochastic simulations suggested that a small movement bias towards the parasite dramatically reduces the number of CD8 T cells needed to eliminate all malaria liver stages, but to detect such attraction requires extremely long imaging experiments. We thus have established a framework for how attraction of moving cells towards a location can be rigorously evaluated.