Estimating the In Vivo Killing Efficacy of Cytotoxic T Lymphocytes across Different Peptide-MHC Complex Densities

Victor Garcia, Kirsten Richter, Frederik Graw, Annette Oxenius and Roland R Regoes

PLOS Computational Biology, 2015, vol. 11, issue 5, 1-19

Abstract: 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.Author Summary: The immune system reacts to the presence of a viral pathogen within the host by the elicitation of an immune response. This response is characterized by the activation and proliferation of specific cell types, which, for instance, produce neutralizing antibodies or kill cells infected by the virus. Cytotoxic T lymphocytes (CTLs) function as an important protecting element of the system by recognizing and clearing infected viral target cells. Surprisingly, estimates of the killing efficacy of CTLs vary about four orders of magnitude across experimental methods and viral systems. In some studies, CTL killing efficacies were estimated by employing pre-treated cells that mimick virus infected cells. In general, cells signal their infection by a pathogen to the immune system by presenting viral peptides on their cellular surface. For the experimentally pretreated cells, these peptides were artificially loaded onto the surface at very high densities. In this paper, we study to what extent the variation in peptide densities can explain the variation found in killing efficacy estimates across methods and viral systems. We found that peptide densities explain only up to two orders of magnitude in killing efficacy variation. The remaining variation must originate from other sources, which might be specific to the viral study system.

Date: 2015
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pcbi00:1004178

DOI: 10.1371/journal.pcbi.1004178

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