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Estimation of the rate of killing by cytotoxic T lymphocytes in vivo.

ABSTRACT: Cytotoxic T lymphocytes (CTL) help control virus infections by killing virus-infected (target) cells. How fast do CTL find and kill target cells in vivo? Experiments allow us to follow populations of labeled target cells after their transfer into immune mice where they are killed by CTL. Here, we develop models of the migration and killing processes involved in these experiments and use them to quantitatively analyze the in vivo killing data. These models allow us to estimate the rate constant for killing of target cells by CTL.

SUBMITTER: Regoes RR

PROVIDER: S-EPMC1785271 | biostudies-literature | 2007 Jan

REPOSITORIES: biostudies-literature

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Estimation of the rate of killing by cytotoxic T lymphocytes in vivo.

Regoes Roland R RR Barber Daniel L DL Ahmed Rafi R Antia Rustom R

Proceedings of the National Academy of Sciences of the United States of America 20070122 5

Cytotoxic T lymphocytes (CTL) help control virus infections by killing virus-infected (target) cells. How fast do CTL find and kill target cells in vivo? Experiments allow us to follow populations of labeled target cells after their transfer into immune mice where they are killed by CTL. Here, we develop models of the migration and killing processes involved in these experiments and use them to quantitatively analyze the in vivo killing data. These models allow us to estimate the rate constant f ...[more]

PMID: 17242364

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Project description:Cytotoxic T lymphocytes (CTLs) are important agents in the control of intracellular pathogens, which specifically recognize and kill infected cells. Recently developed experimental methods allow the estimation of the CTL's efficacy in detecting and clearing infected host cells. One method, the in vivo killing assay, utilizes the adoptive transfer of antigen displaying target cells into the bloodstream of mice. Surprisingly, killing efficacies measured by this method are often much higher than estimates obtained by other methods based on, for instance, the dynamics of escape mutations. In this study, we investigated what fraction of this variation can be explained by differences in peptide loads employed in in vivo killing assays. We addressed this question in mice immunized with lymphocytic choriomeningitis virus (LCMV). We conducted in vivo killing assays varying the loads of the immunodominant epitope GP33 on target cells. Using a mathematical model, we determined the efficacy of effector and memory CTL, as well as CTL in chronically infected mice. We found that the killing efficacy is substantially reduced at lower peptide loads. For physiological peptide loads, our analysis predicts more than a factor 10 lower CTL efficacies than at maximum peptide loads. Assuming that the efficacy scales linearly with the frequency of CTL, a clear hierarchy emerges among the groups across all peptide antigen concentrations. The group of mice with chronic LCMV infections shows a consistently higher killing efficacy per CTL than the acutely infected mouse group, which in turn has a consistently larger efficacy than the memory mouse group. We conclude that CTL killing efficacy dependence on surface epitope frequencies can only partially explain the variation in in vivo killing efficacy estimates across experimental methods and viral systems, which vary about four orders of magnitude. In contrast, peptide load differences can explain at most two orders of magnitude.

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Estimation of the rate of killing by cytotoxic T lymphocytes in vivo.

Publications

Estimation of the rate of killing by cytotoxic T lymphocytes in vivo.

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