Tissue Dimensionality Influences the Functional Response of Cytotoxic T Lymphocyte-Mediated Killing of Targets

Gadhamsetty, Saikrishna; Marée, Athanasius F. M.; Boer, Rob J. de; Beltman, Joost B.

doi:10.3389/fimmu.2016.00668

Cited by 11 publications

(9 citation statements)

References 26 publications

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“…We developed spatial simulations of CTLs killing in microwells, with the aim of generating noisy and undersampled artificial data representative of data generated by microscopy, data which can be used to test methods for recovery of parameters governing CTL hitting. To this end we employed the cellular Potts model (CPM) framework [ 34 ], a formalism we used previously to simulate T cell-target cell interactions [ 11 , 35 , 36 ]. The CPM is a lattice based model, with entities such as cells represented by assigning individual lattice sites a ‘spin’ value, to identify them as belonging to a specific entity.…”

Section: Methodsmentioning

confidence: 99%

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

2020

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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 recent in 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 observed in vitro . We found that multiple-hitting from CTLs was entirely consistent with the observed killing kinetics. Moreover, the number of available targets and the spatiotemporal kinetics of CTL:target interactions influenced the realised CTL killing rate. We subsequently used realistic, spatial simulations to assess methods for estimating the hitting rate and the number of hits required for target death, to be applied to microscopy data of individual CTLs killing targets. We found that measuring the cumulative duration of individual contacts that targets have with CTLs would substantially improve accuracy when estimating the killing kinetics of CTLs.

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Section: Methodsmentioning

confidence: 99%

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

2020

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“…It is widely accepted in immunology that the physiological function of cytotoxic T cell (CTL) motility is to search for target cells, i.e., for virus-infected cells or cancer cells (15). Computational modeling studies have revealed that the search efficiency depends on the organization of the stromal environment of a tissue (16). In addition, the spatial behavior, for example, of HIV-infected target cells scanned for foreign antigens by CTLs strongly impacts the elimination efficiency of the infected targets (17, 18).…”

Section: Introductionmentioning

confidence: 99%

Spatial Lymphocyte Dynamics in Lymph Nodes Predicts the Cytotoxic T Cell Frequency Needed for HIV Infection Control

et al. 2019

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The surveillance of host body tissues by immune cells is central for mediating their defense function. In vivo imaging technologies have been used to quantitatively characterize target cell scanning and migration of lymphocytes within lymph nodes (LNs). The translation of these quantitative insights into a predictive understanding of immune system functioning in response to various perturbations critically depends on computational tools linking the individual immune cell properties with the emergent behavior of the immune system. By choosing the Newtonian second law for the governing equations, we developed a broadly applicable mathematical model linking individual and coordinated T-cell behaviors. The spatial cell dynamics is described by a superposition of autonomous locomotion, intercellular interaction, and viscous damping processes. The model is calibrated using in vivo data on T-cell motility metrics in LNs such as the translational speeds, turning angle speeds, and meandering indices. The model is applied to predict the impact of T-cell motility on protection against HIV infection, i.e., to estimate the threshold frequency of HIV-specific cytotoxic T cells (CTLs) that is required to detect productively infected cells before the release of viral particles starts. With this, it provides guidance for HIV vaccine studies allowing for the migration of cells in fibrotic LNs.

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“…Nevertheless, our qualitative conclusions are also valid for 3D simulations for two reasons. First, the differences between 2D and 3D killing rates are quantitative rather than qualitative because encounter of targets by CTLs is more efficient in 3D spaces ( 19 , 20 ). Second, we find similar results in ODE models that consider well-mixed environments of arbitrary dimension.…”

Section: Discussionmentioning

confidence: 99%

A Sigmoid Functional Response Emerges When Cytotoxic T Lymphocytes Start Killing Fresh Target Cells

Gadhamsetty

Marée

Beltman

et al. 2017

Biophysical Journal

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Cytotoxic T lymphocyte (CTL)-mediated killing involves the formation of a synapse with a target cell, followed by delivery of perforin and granzymes. Previously, we derived a general functional response for CTL killing while considering that CTLs form stable synapses (i.e., single-stage) and that the number of conjugates remains at steady state. However, the killing of target cells sometimes requires multiple engagements (i.e., multistage). To study how multistage killing and a lack of steady state influence the functional response, we here analyze a set of differential equations as well as simulations employing the cellular Potts model, in both cases describing CTLs that kill target cells. We find that at steady state the total killing rate (i.e., the number of target cells killed by all CTLs) is well described by the previously derived double saturation function. Compared to single-stage killing, the total killing rate during multistage killing saturates at higher CTL and target cell densities. Importantly, when the killing is measured before the steady state is approached, a qualitatively different functional response emerges for two reasons: First, the killing signal of each CTL gets diluted over several targets and because this dilution effect is strongest at high target cell densities; this can result in a peak in the dependence of the total killing rate on the target cell density. Second, the total killing rate exhibits a sigmoid dependence on the CTL density when killing is a multistage process, because it takes typically more than one CTL to kill a target. In conclusion, a sigmoid dependence of the killing rate on the CTLs during initial phases of killing may be indicative of a multistage killing process. Observation of a sigmoid functional response may thus arise from a dilution effect and is not necessarily due to cooperative behavior of the CTLs.

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Tissue Dimensionality Influences the Functional Response of Cytotoxic T Lymphocyte-Mediated Killing of Targets

Cited by 11 publications

References 26 publications

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

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

Spatial Lymphocyte Dynamics in Lymph Nodes Predicts the Cytotoxic T Cell Frequency Needed for HIV Infection Control

A Sigmoid Functional Response Emerges When Cytotoxic T Lymphocytes Start Killing Fresh Target Cells

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