Estimating In Vivo Death Rates of Targets due to CD8 T-Cell-Mediated Killing

Abstract

ABSTRACT Despite recent advances in immunology, several key parameters determining virus dynamics in infected hosts remain largely unknown. For example, the rate at which specific effector and memory CD8 T cells clear virus-infected cells in vivo is hardly known for any viral infection. We propose a framework to quantify T-cell-mediated killing of infected or peptide-pulsed target cells using the widely used in vivo cytotoxicity assay. We have reanalyzed recently published data on killing of peptide-pulsed splenocytes by cytotoxic T lymphocytes and memory CD8 T cells specific to NP396 and GP276 epitopes of lymphocytic choriomeningitis virus (LCMV) in the mouse spleen. Because there are so many effector CD8 T cells in spleens of mice at the peak of the immune response, NP396- and GP276-pulsed targets are estimated to have very short half-lives of 2 and 14 min, respectively. After the effector numbers have diminished, i.e., in LCMV-immune mice, the half-lives become 48 min and 2.8 h for NP396- and GP276-expressing targets, respectively. Analysis of several alternative models demonstrates that the estimates of half-life times of peptide-pulsed targets are not affected when changes are made in the model assumptions. Our report provides a unifying framework to compare killing efficacies of CD8 T-cell responses specific to different viral and bacterial infections in vivo, which may be used to compare efficacies of various cytotoxic-T-lymphocyte-based vaccines.