Induction of CD4 T cell memory by local cellular collectivity

Polonsky, Michal; Rimer, Jacob; Kern-Perets, Amos; Zaretsky, Irina; Miller, Stav; Bornstein, Chamutal; David, Eyal; Kopelman, Naama M.; Stelzer, Gil; Porat, Ziv; Chain, Benjamin M.; Friedman, Nir

doi:10.1126/science.aaj1853

Cited by 74 publications

(79 citation statements)

References 52 publications

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“…Another recent study suggested that early IL-2 produced by nascent Tfh/T CM precursors signaled in a paracrine manner to CD25 hi counterparts, which supported Th1 differentiation. 25 This study raises the possibility that local signals mediated by IL-2 between adjacent CD4 + T cells can influence fate, a theme explored in vitro by Polonsky et al 26 In that study, IL-2 produced by a quorum of neighboring CD4 + T cells triggered the expression of CD62L, employed as a marker of T CM cells. 26 These findings appear to sit at odds with a model in which IL-2 signaling supports effector CD4 + T cells and T EM cells, not T CM cells.…”

Section: Controlling the Development Of Cd4 + T-cell Memorymentioning

confidence: 86%

Development of circulating CD4⁺ T‐cell memory

et al. 2019

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The ability of circulating CD4+ T cells to retain memories of previous antigenic encounters is a cardinal feature of the adaptive immune system. Over the past two decades, since the first description of central and effector memory T cells, many studies have examined molecular mechanisms controlling CD8+ T‐cell memory, with comparatively less research into CD4+ T‐cell memory. Here, we review a number of seminal studies showing that circulating memory CD4+ T cells develop directly from effector cells; and in so doing, preserve features of their effector precursors. We examine mechanisms controlling the development and phenotypes of memory CD4+ T cells, and provide an updated model that accommodates both the central and effector memory paradigm and the diverse T helper cell classification system.

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Section: Controlling the Development Of Cd4 + T-cell Memorymentioning

confidence: 86%

Development of circulating CD4⁺ T‐cell memory

et al. 2019

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“…N prod > 1, 000. This estimate illustrates that there exist thresholds of activation for immune responses, whereby the systems needs a critical mass of activated, cytokinesecreting cells to overcome consumption and drive activation and differentiation [86]. The estimate above does not take into account some of the intricacies of IL-2 regulation: positive feedback in IL-2 secretion, recycling of IL2Rα chains, upregulation of IL-2R in T reg cells have been documented.…”

Section: Regulation By Cytokine Consumptionmentioning

confidence: 96%

“…Recent experiments have revisited the question of naive T-cells differentiation into different memory cell types upon antigen stimulation, by considering collective effects through cell-cell communication. Polonsky et al [86] tracked live cells tagged with antibody markers over time in microwells with different initial cell numbers. By continuously tracking individual cell differentiation states and proliferation, they are able to overcome the limitations of bulk experiments where local cell densities are hard to control.…”

Section: Quorum Sensingmentioning

confidence: 99%

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Quantitative Immunology for Physicists

Altan‐Bonnet

Mora

Walczak

2019

Preprint

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The adaptive immune system is a dynamical, self-organized multiscale system that protects vertebrates from both pathogens and internal irregularities, such as tumours. For these reason it fascinates physicists, yet the multitude of different cells, molecules and sub-systems is often also petrifying. Despite this complexity, as experiments on different scales of the adaptive immune system become more quantitative, many physicists have made both theoretical and experimental contributions that help predict the behaviour of ensembles of cells and molecules that participate in an immune response. Here we review some recent contributions with an emphasis on quantitative questions and methodologies. We also provide a more general methods section that presents some of the wide array of theoretical tools used in the field. CONTENTS Dissociation ratesAs discussed below, immunological interactions span the range of very short lived interactions, k off > 10 s −1 or τ off = (k off ) −1 < 0.1 s for antibody binding to its target in the initial phase of an immune response, to extremely long-lived interactions, k off < 10 −4 s −1 or τ off > 3 hours for cytokines interacting with their receptors. These estimates set a huge range of time scales the immune system must deal with, even before taking into consideration delays in cellular responses and how these affect the ligand environment on time scales ranging from hours to days. These considerations form the crux of the matter for quantitative immunology at the cellular scale: while the physical chemistry of ligand-receptor interactions is straightforward, the immune system builds a response of devilish complexity from such elementary interactions. Numbers of receptors per cellIn some situations, such as in T cell antigen recognition, where both the T cell receptor and the antigen exist in a membrane-bound form. All dynamics of interactions must be estimated taking into account the surface concentrations of molecules, with proper adjustment for slower diffusion in the association rates.

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“…to the progenitor-exhausted state (Miller et al, 2019) and to the tuning of the critical number of T cells 82 required for proper differentiation (Polonsky et al, 2018). 83…”

mentioning

confidence: 99%

SLAMF6 deficiency augments tumor killing and skews towards an effector phenotype revealing it as a novel T cell checkpoint

Hajaj

Eisenberg

Klein

et al. 2019

Preprint

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SLAMF6 is a homotypic receptor of the Ig-superfamily whose exact role in immune modulation has remained elusive. Its constitutive expression on resting and activated T cells precludes it from being a bona fide exhaustion marker. By breeding Pmel-1 mice with SLAMF6 KO mice, we generated donors for T cells lacking SLAMF6 and expressing a transgenic TCR for gp100-melanoma antigen. Activated Pmel-1xSLAMF6 KO CD8 T cells displayed improved polyfunctionality and strong tumor cytolysis. T-bet was the dominant transcription factor in Pmel-1xSLAMF6 KO cells, and upon activation, they acquired an effector-memory phenotype. Blocking LAG-3 improved the function of SLAMF6 deficient T cells even further. Finally, adoptive transfer of Pmel-1xSLAMF6 KO T cells into melanoma-bearing mice resulted in lasting tumor regression in contrast to temporary responses achieved with Pmel-1 T cells. These results support the notion that SLAMF6 is an inhibitory immune receptor whose absence enables powerful CD8 T cells to eradicate tumors.

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Induction of CD4 T cell memory by local cellular collectivity

Cited by 74 publications

References 52 publications

Development of circulating CD4⁺ T‐cell memory

Development of circulating CD4⁺ T‐cell memory

Quantitative Immunology for Physicists

SLAMF6 deficiency augments tumor killing and skews towards an effector phenotype revealing it as a novel T cell checkpoint

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Induction of CD4 T cell memory by local cellular collectivity

Cited by 74 publications

References 52 publications

Development of circulating CD4+ T‐cell memory

Development of circulating CD4+ T‐cell memory

Quantitative Immunology for Physicists

SLAMF6 deficiency augments tumor killing and skews towards an effector phenotype revealing it as a novel T cell checkpoint

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Product

Resources

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Development of circulating CD4⁺ T‐cell memory

Development of circulating CD4⁺ T‐cell memory