A tissue-like platform for studying engineered quiescent human T-cells’ interactions with dendritic cells

Abu-Shah, Enas; Demetriou, Philippos; Bálint, Štefan; Mayya, Viveka; Kutuzov, Mikhail A.; Dushek, Omer; Dustin, Michael L.

doi:10.7554/elife.48221

Cited by 16 publications

(24 citation statements)

References 30 publications

(35 reference statements)

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“…Using systematic experiments in a reductionist plate-based system, with precise control of pMHC antigen dose/affinity and co-stimulation through CD28, CD2, and CD27, we found no evidence for different antigen thresholds for different cytokines produced by CD8 + T cell blasts. We observed similar results when using memory CD8 + T cells stimulated by monocyte-derived antigen presenting cells expressing a host of co-signalling receptor ligands (12).…”

Section: Discussionsupporting

confidence: 72%

“…By incorporating ligands to CD28, CD2, and CD27, we show that although they increase cytokine production, they do so similarly for different cytokines so that the threshold remains comparable. Finally, we reproduce these findings in a recently described experimental system (12) that allows for the study of quiescent primary memory CD8 + T cells responding to autologous monocyte-derived dendritic cells. The work suggests a conceptually simpler phenotypic model for TCR signalling with implications for the role of antigen concentration and affinity in mediating T cell responses.…”

Section: Introductionmentioning

confidence: 61%

“…T cells-Antigen presenting cells stimulation assay. The assay was performed as previously described (12). Briefly, memory CD8 + T cells were isolated from anonymised leukapheresis products obtained from the NHS at Oxford University Hospitals by (REC 11/H0711/7), using memory CD8 + isolation kit (StemCell Technologies).…”

Section: Methodsmentioning

confidence: 99%

“…6A). This experimental system has recently been described in detail (12). We focused on memory CD8 + T cells because naive T cells do not produce cytokines on our experimental timescales (24).…”

Section: Different Cytokines Exhibit Comparable Antigen Dose Thresholmentioning

confidence: 99%

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Human CD8⁺T cells exhibit a shared antigen threshold for different effector responses

Abu-Shah

Trendel

Krüger

et al. 2020

Preprint

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T cells recognising cognate pMHC antigens become activated to elicit a myriad of cellular responses, such as target cell killing and the secretion of different cytokines, that collectively contribute to adaptive immunity. These effector responses have been hypothesised to exhibit different antigen dose and affinity thresholds, suggesting that pathogen-specific information may be encoded within the nature of the antigen. Here, using systematic experiments in a reductionist system, where primary human CD8 + T cell blasts are stimulated by recombinant pMHC antigen alone, we show that different inflammatory cytokines have comparable antigen dose thresholds across a 25,000-fold variation in affinity. Although co-stimulation by CD28, CD2, and CD27 increased cytokine production in this system, the antigen threshold remained comparable across different cytokines. When using primary human memory CD8 + T cells responding to autologous antigen presenting cells equivalent thresholds were also observed for cytokine production and killing. These findings imply a simple phenotypic model of TCR signalling where multiple T cell responses share a common rate-limiting threshold and a conceptually simple model of antigen recognition, where the chance factor of antigen dose and affinity do not provide any additional response-specific information.

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Section: Discussionsupporting

confidence: 72%

Section: Introductionmentioning

confidence: 61%

Section: Methodsmentioning

confidence: 99%

Section: Different Cytokines Exhibit Comparable Antigen Dose Thresholmentioning

confidence: 99%

See 2 more Smart Citations

Human CD8⁺T cells exhibit a shared antigen threshold for different effector responses

Abu-Shah

Trendel

Krüger

et al. 2020

Preprint

Self Cite

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“…12 The technology has been improved by the employment of checkpoint inhibitors for 'immune checkpoint blockade' 13 and depletion of patients' existing in vivo T cell populations (lympho-depletive regimes) 14 prior to infusion of their own T cells, 15 which may have been engineered to match tumour antigens. 16,17 While tumour infiltrating lymphocytes have long been studied in this context, 8 peripheral blood mononuclear cells (PBMC) are proving a better T cell source since they are at a developmental stage less prone to metabolic 'exhaustion', an antigen dose-dependent tolerogenic process that is likely in tumour microenvironments. 10,11,18 As with peripheral immune system T cells generally, cultured PBMC can be activated to transform and divide by lectins.…”

mentioning

confidence: 99%

Metabolic optimization of adoptive T cell transfer cancer immunotherapy: A historical overview

Forsdyke

2020

Scand J Immunol

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After prolonged extracorporeal multiplication in physiological culture media, there can be curative infusions of a cancer patient's own cytotoxic T cells (adoptive T cell transfer; ACT), which must achieve efficient activation in potentially adverse tumour microenvironments. With spectacular, yet irregular, success, improvements are needed. Developing lymphoid cells are biologically selected, not only for ‘near‐self’ reactivity (positive selection), but also to avoid self‐reactivity (negative selection). Thus, success requires harnessing near‐self cells while avoiding extreme autoimmune phenomena. Abrupt metabolic changes accompanying T cell activation to leave the G0 stage and enter the G1 stage of the cell cycle (eg enhanced glycolysis) are accompanied by increased transcription of the G0S9 gene that mediates salvage synthesis of NAD+ from nicotinamide; the latter has recently been shown to increase the efficiency of ACT. Despite theoretical and experimental advances, there has not been parallel progress in simulating in vivo conditions with culture media that were initially formulated for their positive benefits for tumour cell lines (cell survival and proliferation). Yet for lymphoid cells, inhibition or death (ie immunological tolerance) is as important as their activation and proliferation (immunological response). Thus, use of media optimized for the latter may mask the former. The resilience of established culture protocols may have been partly politically driven. However, unphysiological conditions have sometimes yielded fortuitous insights. Optimization of culture media for specific tissues must consider the nature of problems addressed in research settings and the need to avoid mishaps in clinical settings.

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Artificial Biosystem for Modulation of Interactions between Antigen‐Presenting Cells and T Cells

et al. 2020

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T cell activation is triggered by signal molecules on the surface of antigen‐presenting cells (APC) and subsequent exertion of cellular forces. Deciphering the biomechanical and biochemical signals in this complex process is of interest and will contribute to an improvement in immunotherapy strategies. To address underlying questions, coculture and biomimetic models are established. Mature dendritic cells (mDC) are first treated with cytochalasin B (CytoB), a cytoskeletal disruption agent known to lower apparent cellular stiffness and reduction in T cell proliferation is observed. It is attempted to mimic mDC and T cell interactions using polyacrylamide (PA) gels with defined stiffness corresponding to mDC (0.2–25 kPa). Different ratios of anti‐CD3 (aCD3) and anti‐CD28 (aCD28) antibodies are immobilized onto PA gels. The results show T cell proliferation is triggered by both aCD3 and aCD28 in a stiffness‐dependent manner. Cells cultured on aCD3 immobilized on gels has significantly enhanced proliferation and IL‐2 secretion, compared to aCD28. Furthermore, ZAP70 phosphorylation is enhanced in stiffer substrate a in a aCD3‐dependent manner. The biosystem provides an approach to study the reduction of T cell proliferation observed on CytoB‐treated mDC. Overall, the biosystem allows distinguishing the impact of biophysical and biochemical signals of APC and T cell interactions in vitro.

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A tissue-like platform for studying engineered quiescent human T-cells’ interactions with dendritic cells

Cited by 16 publications

References 30 publications

Human CD8⁺T cells exhibit a shared antigen threshold for different effector responses

Human CD8⁺T cells exhibit a shared antigen threshold for different effector responses

Metabolic optimization of adoptive T cell transfer cancer immunotherapy: A historical overview

Artificial Biosystem for Modulation of Interactions between Antigen‐Presenting Cells and T Cells

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A tissue-like platform for studying engineered quiescent human T-cells’ interactions with dendritic cells

Cited by 16 publications

References 30 publications

Human CD8+T cells exhibit a shared antigen threshold for different effector responses

Human CD8+T cells exhibit a shared antigen threshold for different effector responses

Metabolic optimization of adoptive T cell transfer cancer immunotherapy: A historical overview

Artificial Biosystem for Modulation of Interactions between Antigen‐Presenting Cells and T Cells

Contact Info

Product

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Human CD8⁺T cells exhibit a shared antigen threshold for different effector responses

Human CD8⁺T cells exhibit a shared antigen threshold for different effector responses