Evaluation of CD8 T cell killing models with computer simulations of 2-photon imaging experiments

PLoS Comput Biol. 2020 Dec 28;16(12):e1008428. doi: 10.1371/journal.pcbi.1008428. eCollection 2020 Dec.

Abstract

In vivo imaging of cytotoxic T lymphocyte (CTL) killing activity revealed that infected cells have a higher observed probability of dying after multiple contacts with CTLs. We developed a three-dimensional agent-based model to discriminate different hypotheses about how infected cells get killed based on quantitative 2-photon in vivo observations. We compared a constant CTL killing probability with mechanisms of signal integration in CTL or infected cells. The most likely scenario implied increased susceptibility of infected cells with increasing number of CTL contacts where the total number of contacts was a critical factor. However, when allowing in silico T cells to initiate new interactions with apoptotic target cells (zombie contacts), a contact history independent killing mechanism was also in agreement with experimental datasets. The comparison of observed datasets to simulation results, revealed limitations in interpreting 2-photon data, and provided readouts to distinguish CTL killing models.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • CD8-Positive T-Lymphocytes / immunology*
  • Cytotoxicity, Immunologic*
  • Humans
  • Photons

Grant support

AR was supported by the Helmholtz International Graduate School for Infection Research, grant number VHGS-202. PR was supported by the Human Frontier Science Program (RGP0033/2015). In vivo experiments and imaging which were carried out by SH were funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – Projektnummer 158989968 - SFB 900 (projects B1 and B3). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.