Individual Human Cytotoxic T Lymphocytes Exhibit Intraclonal Heterogeneity during Sustained Killing

Vasconcelos, Zilton; Müller, Sabina; Guipouy, Delphine; Yu, Wong; Christophe, Claire; Gadat, Sébastien; Valitutti, Salvatore; Dupré, Loı̈c

doi:10.1016/j.celrep.2015.05.002

Cited by 45 publications

(60 citation statements)

References 26 publications

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“…The CTL contact integration hypothesis naturally gives rise to a diverse population of CTLs that show heterogeneity during killing. This is in agreement with studies showing that CTLs have dissimilar killing properties that contribute to a robust T cell response ( [21], [22]).…”

Section: Discussionsupporting

confidence: 92%

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

Rastogi

Robert

Halle

et al. 2019

Preprint

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Highlights• Killing of infected cells by cytotoxic T cells typically involves more than a single contact.• Cytotoxic T cells or infected cells integrate signals from multiple interactions.• T cell contacts with dying infected cells have a major impact on in vivo data interpretation. AbstractIn 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, suggesting memory effect in CTLs or infected cells. We developed a three-dimensional agent-based model of CTL killing activity 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 as opposed to signal integration over many contacts. However, when allowing in silico T cells to interact with apoptotic target cells (zombie contacts), a contact history independent killing mechanism was also in agreement with the experimental datasets. We showed that contacts that take place between CTLs and dying infected cells impact the observed killing dynamics because even in absence of modulation of cell properties, we saw an increase of the observed probability of killing infected cells with more interactions. The duration taken by an infected cell to die and the per capita killing rate (PCKR) of CTLs, parameters hard to measure directly, were determined from the model and turned out predictive to distinguish the different CTL killing models in future experiments. The comparison of observed datasets to simulation results, revealed limitations in interpreting 2-photon data, and provided prediction for additional measurements to distinguish CTL killing models. Significance StatementDespite having a clear understanding of cytotoxic T lymphocyte (CTL) mediated cytotoxicity mechanisms, the quantitative dynamics remain unexplored at a cellular level. We developed an agentbased model to compare different hypotheses for mechanisms of CTL mediated cytotoxicity that could lead to an increase in observed probability of killing infected cells at higher interactions with CTLs as seen in vivo. We showed that this behaviour can be explained by modulation of properties by infected cells or CTLs with increasing number of contacts. For the modulation, we compared two modes of signal integration and showed that time is not a relevant parameter in signal integration. We also studied the impact of contacts between CTLs and apoptotic infected cells on observed killing properties.

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Section: Discussionsupporting

confidence: 92%

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

Rastogi

Robert

Halle

et al. 2019

Preprint

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“…However, such data provide only indirect information on T cell function. There is evidence that the killing activity may largely differ between individual T cells, and that “super killers” may dominate in cytotoxicity assays45, meaning that many other T cells do not contribute significantly to target cell killing. For characterization of T cells and their degree of heterogeneity, it is much preferable to have direct information of T cells, with similar data weight for each individual cell.…”

Section: Discussionmentioning

confidence: 99%

Heterogeneity assessment of functional T cell avidity

Ioannidou

Baumgaertner

Gannon

et al. 2017

Sci Rep

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The potency of cellular immune responses strongly depends on T cell avidity to antigen. Yet, functional avidity measurements are rarely performed in patients, mainly due to the technical challenges of characterizing heterogeneous T cells. The mean functional T cell avidity can be determined by the IFN-γ Elispot assay, with titrated amounts of peptide. Using this assay, we developed a method revealing the heterogeneity of functional avidity, represented by the steepness/hillslope of the peptide titration curve, documented by proof of principle experiments and mathematical modeling. Our data show that not only natural polyclonal CD8 T cell populations from cancer patients, but also monoclonal T cells differ strongly in their heterogeneity of functional avidity. Interestingly, clones and polyclonal cells displayed comparable ranges of heterogeneity. We conclude that besides the mean functional avidity, it is feasible and useful to determine its heterogeneity (hillslope) for characterizing T cell responses in basic research and patient investigation.

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“…His group has published evidence that melanoma cells need longer interaction times with CTLs and multiple interactions with CTLs to be lysed. 5,6 This resistance mechanism involves two interesting phenomena: less intake of granzyme B into the cytoplasm of tumor cells and the ability of melanoma cells to polarize late endosomal lysosomal (LLE) vesicles toward interacting CTLs. Moreover, this group's experimentation showed that the proteases in these vesicles were able to degrade the perforin directionally secreted by CTLs.…”

Section: Understanding and Exploiting Cytotoxicitymentioning

confidence: 99%

Cellular immunotherapies for cancer

et al. 2017

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Lessons learned over decades on the use of gene and cell therapies have found clinical applicability in the field of cancer immunotherapy. On December 16, 2016 a symposium was held in Pamplona (Spain) to analyze and discuss the critical points for the clinical success of adoptive cell transfer strategies in cancer immunotherapy. Cellular immunotherapy is being currently exploited for the development of new cancer vaccines using manipulated dendritic cells or to enhance the number of effector cells, transferring reinvigorated NK cells or T cells. In this meeting report, we summarize the main topics covered and provide an overview of the field of cellular immunotherapy.

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Individual Human Cytotoxic T Lymphocytes Exhibit Intraclonal Heterogeneity during Sustained Killing

Cited by 45 publications

References 26 publications

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

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

Heterogeneity assessment of functional T cell avidity

Cellular immunotherapies for cancer

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