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Publication type: Article in scientific journal
Type of review: Peer review (publication)
Title: Estimating the in vivo killing efficacy of cytotoxic T lymphocytes across different peptide-MHC complex densities
Authors: Garcia, Victor
Richter, Kirsten
Graw, Frederik
Oxenius, Annette
Regoes, Roland R.
DOI: 10.21256/zhaw-4704
Published in: PLOS Computational Biology
Volume(Issue): 11
Issue: 5
Pages: 1
Pages to: 13
Issue Date: May-2015
Publisher / Ed. Institution: Public Library of Science
ISSN: 1553-7358
Language: English
Subjects: Adoptive transfer; Animals; Viral antigens; Computational biology; Immunologic cytotoxicity; Epitopes; Host-pathogen interactions; Lymphocytic choriomeningitis; Lymphocytic choriomeningitis virus; Major histocompatibility complex; Mice; Peptides; Cytotoxic T-lymphocytes; Viral proteins; Immunological models
Subject (DDC): 571: Physiology and related subjects
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.
Fulltext version: Published version
License (according to publishing contract): CC BY 4.0: Attribution 4.0 International
Departement: Life Sciences and Facility Management
Organisational Unit: Institute of Applied Simulation (IAS)
Appears in collections:Publikationen Life Sciences und Facility Management

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