Heterogeneous, delayed-onset killing by multiple-hitting T cells: Stochastic simulations to assess methods for analysis of imaging data

by Richard J. Beck, Dario I. Bijker, Joost B. Beltman

Although quantitative insights into the killing behaviour of Cytotoxic T Lymphocytes (CTLs) are necessary for the rational design of immune-based therapies, CTL killing function remains insufficiently characterised. One established model of CTL killing treats CTL cytotoxicity as a Poisson process, based on the assumption that CTLs serially kill antigen-presenting target cells via delivery of lethal hits, each lethal hit corresponding to a single injection of cytotoxic proteins into the target cell cytoplasm. Contradicting this model, a recentin vitro study of individual CTLs killing targets over a 12-hour period found significantly greater heterogeneity in CTL killing performance than predicted by Poisson-based killing. The observed killing process was dynamic and varied between CTLs, with the best performing CTLs exhibiting a marked increase in killing during the final hours of the experiments, along with a “burst killing” kinetic. Despite a search for potential differences between CTLs, no mechanistic explanation for the heterogeneous killing kinetics was found. Here we have used stochastic simulations to assess whether target cells might require multiple hits from CTLs before undergoing apoptosis , in order to verify whether multiple-hitting could explain the late onset, burst killing dynamics observedin vitro. We found that multiple-hitting from CTLs was entirely consistent with the observed killing kinetics. More...

Source: PLoS Computational Biology - July 12, 2020 Category: Biology Authors: Richard J. Beck Source Type: research