Abstract
Vaccination strategies in mice inducing high numbers of memory CD8 T cells specific to a single epitope are able to provide sterilizing protection against infection with Plasmodium sporozoites. We have recently suggested that formation of clusters of activated/memory CD8 T cells around Plasmodium-infected hepatocytes is important in providing such protection. While we have shown that 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 cell 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 in which we employed intravital microscopy to longitudinally image 32 GFP-expressing Plasmodium yoelii parasites in livers of mice that had received activated Plasmodium-specific CD8 T cells after sporozoite infection. We found great heterogeneity in the dynamics of the normalized GFP signal from the parasites (termed “vitality index” or VI) that was weakly correlated with the number of T cells near the parasite. We found that a simple model assuming mass-action killing by independent T cells relatively well describes the decay of VI over time for a subset of parasites (8/32). Given the estimated average per capita kill rate of k = 0.049/h even a single T cell should be able to kill the parasite in 48 hour lifespan of the liver stage. Stochastic simulations suggested that the observed constant VI in the majority of parasites cannot be explained with the estimated kill rate and the 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 CD8 T cells control individual intracellular infections in vivo.
Competing Interest Statement
The authors have declared no competing interest.
Abbreviations
- IPy
- Plasmodium yoelii
- GFP
- green fluorescent protein
- VI
- vitality index
- DDR
- density-dependent recruitment.