Abstract
Cytotoxic T lymphocytes (CTLs) are important immune effectors against intra-cellular pathogens. These cells search for infected cells and kill them. Recently developed experimental methods in combination with mathematical models allow for the quantification of the efficacy of CTL killing in vivo and, hence, for the estimation of parameters that characterize the effect of CTL killing on the target cell populations. It is not known how these population-level parameters relate to single-cell properties. To address this question, we developed a three-dimensional cellular automaton model of the region of the spleen where CTL killing takes place. The cellular automaton model describes the movement of different cell populations and their interactions. Cell movement patterns in our cellular automaton model agree with observations from two-photon microscopy. We find that, despite the strong spatial nature of the kinetics in our cellular automaton model, the killing of target cells by CTLs can be described by a term which is linear in the target cell frequency and saturates with respect to the CTL levels. Further, we find that the parameters describing CTL killing on the population level are most strongly impacted by the time a CTL needs to kill a target cell. This suggests that the killing of target cells, rather than their localization, is the limiting step in CTL killing dynamics given reasonable frequencies of CTL. Our analysis identifies additional experimental directions which are of particular importance to interpret estimates of killing rates and could advance our quantitative understanding of CTL killing.
Highlights
Cytotoxic T lymphocytes (CTL) are some of the most important cells of our immune system
By varying the individual properties of simulated CTLs, such as the velocity, we find that the time a CTL needs to kill an infected cell is probably the key factor limiting CTL killing efficacy
Studying the influence of single cell properties on our killing rate estimates we find that one specific experimental detail, which concerns the fate of CTL-target cell conjugates after splenectomy, is of particular importance to be able to interpret the populationlevel killing rate constants in terms of single cell efficacy
Summary
Cytotoxic T lymphocytes (CTL) are some of the most important cells of our immune system. They are important against viral infections or tumours. They recognize infected cells by scanning their surfaces for peptide-MHC-I complexes which present peptide fragments sampled from the cytoplasm. These complexes can tell the CTL if the cell is infected or not. Once activated and primed for a specific peptide-MHC-I complex, CD8+ T cells differentiate into effector CTL, which are able to lyse infected cells. After an infection is cleared, some specific CTL may persist as memory cells
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