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Center for Nonlinear Studies |
Vaccination strategies in mice inducing high levels of memory CD8 T cells specific to a singleepitope are able to provide sterilizing protection against malaria infection. We have recentlysuggested that the formation of clusters of activated/memory CD8 T cells around malaria-infected hepatocytes is important in providing such protection. While we have shown that the formation of such clusters is relatively rapid, many questions of how clustered CD8 T cells eliminate the infection remain unanswered. Specifically, we still do not know if one T can kill the parasite, how long it takes for T cells to eliminate the infection, and whether individual T cells in the cluster cooperate or compete in killing the parasite. To address these questions, we used our previously generated data. We used intravital microscopy to longitudinally image 32 parasites in livers of mice that had received malaria-specific CD8 T cells. We found significant heterogeneity in the dynamics of the normalized GFP signal from the parasites (termed “vitality index†or VI) that was poorly correlated with the number of clustered T cells around the parasite. We found a simple model assuming mass-action killing by independent T cells relatively well describes the decay of VI over time, suggesting that even a single T cell should be able to kill the parasite in a 48-hour lifespan of the liver stage. Stochastic simulations indicated that the observed constant VI in majority of parasites cannot be explained with estimated parameters and observed numbers of T cells in clusters suggesting that for such parasites, either T cells do not recognize the infection, or the parasite actively resists killing. Taken together, our analysis provides novel insights into how individual CD8 T cells control intracellular infections in vivo.
Host: Carmen Molina-Paris