Staggered starts in the race to T cell activation

Richard, Alison F.; Frazer, Gordon L.; Claire, Y.; Griffiths, Gillian M.

doi:10.1016/j.it.2021.09.004

Cited by 7 publications

(9 citation statements)

References 143 publications

(230 reference statements)

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“…Time required for commitment to proliferation is determined by TCR-pMHC affinity Na€ ıve CD8 + T cells commit to activation, proliferation, and differentiation after TCR interacts with the cognate pMHC-I presented by APC (Brownlie & Zamoyska, 2013;Cantrell, 2015;Richard et al, 2021). Na€ ıve CD8 + T cells require a short period of exposure to APC expressing the cognate pMHC before initiating a clonal expansion and development program (van Stipdonk et al, 2001).…”

Section: Resultsmentioning

confidence: 99%

Time required for commitment to T cell proliferation depends on TCR affinity and cytokine response

Balyan

Brzostek

et al. 2022

EMBO Reports

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T cell activation and effector functions are determined by the affinity of the interaction between T cell receptor (TCR) and its antigenic peptide MHC (pMHC) ligand. A better understanding of the quantitative aspects of TCR‐pMHC affinity‐dependent T cell activation is critical for the development of new immunotherapeutic strategies. However, the role of TCR‐pMHC affinity in regulating the kinetics of CD8+ T cell commitment to proliferation and differentiation is unknown. Here, we show that the stronger the TCR‐pMHC affinity, the shorter the time of T cell‐APC co‐culture required to commit CD8+ T cells to proliferation. The time threshold for T cell cytokine production is much lower than that for cell proliferation. There is a strong correlation between affinity‐dependent differences in AKT phosphorylation and T cell proliferation. The cytokine IL‐15 increases the poor proliferation of T cells stimulated with low affinity pMHC, suggesting that pro‐inflammatory cytokines can override the affinity‐dependent features of T cell proliferation.

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Section: Resultsmentioning

confidence: 99%

Time required for commitment to T cell proliferation depends on TCR affinity and cytokine response

Balyan

Brzostek

et al. 2022

EMBO Reports

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“…In mature T cells, a rate-limiting switch-like mechanism has been suggested for activation responses after TCR stimulation (49). Experiments using live imaging of individual TCR-ligand interactions found that T cells experienced a wide range of receptor-ligand dwell times, with only very long interactions or sequential, spatially co-localized interactions leading to T cell activation (50).…”

Section: Diversification By Temporal Variationmentioning

confidence: 99%

Divide and Conquer: Phenotypic and Temporal Heterogeneity Within CD8+ T Cell Responses

Richard

2022

Front. Immunol.

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The advent of technologies that can characterize the phenotypes, functions and fates of individual cells has revealed extensive and often unexpected levels of diversity between cells that are nominally of the same subset. CD8+ T cells, also known as cytotoxic T lymphocytes (CTLs), are no exception. Investigations of individual CD8+ T cells both in vitro and in vivo have highlighted the heterogeneity of cellular responses at the levels of activation, differentiation and function. This review takes a broad perspective on the topic of heterogeneity, outlining different forms of variation that arise during a CD8+ T cell response. Specific attention is paid to the impact of T cell receptor (TCR) stimulation strength on heterogeneity. In particular, this review endeavors to highlight connections between variation at different cellular stages, presenting known mechanisms and key open questions about how variation between cells can arise and propagate.

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“…Several studies have demonstrated that T cells respond best when they are stimulated by receptors or bispecific molecules with certain optimal affinities and kinetics, often preferring fast on-rate interactions over those with slow dissociation rates 14 . The detailed mechanisms behind this preference have not been completely elucidated, but several negative feedback mechanisms, such as phosphorylation by inhibitory Src family kinases 1 and recruitment of specific phosphatases 3 , are candidates for converting the TCR-CD3 complex to a signalling-impotent dark-state after a prolonged period of activation 15 .…”

Section: Introductionmentioning

confidence: 99%

“…Target recognition by T cells is governed by the clonally expressed T cell receptor (TCR), which can initiate T cell activation upon binding to a cognate peptide-human leukocyte antigen (pHLA) complex, leading to immune synapse formation, phosphorylation of the CD3 signalling complex and downstream signalling. [2][3][4][5] Importantly, T cells are highly sensitive, and can be activated by very low numbers of cognate pHLA (in the 10s per cell). 4,6,7 Despite their exquisite sensitivity for antigen, TCRs bind to pHLA complex with weak affinity (K D s in the low µM range) and fast kinetics (half-life in seconds).…”

Section: Introductionmentioning

confidence: 99%

Tuning the potency and therapeutic window of ImmTAC molecules by affinity modulation

Robertson

Mulvaney

Dieckmann

et al. 2022

Preprint

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T cell engaging bispecifics have great clinical potential for the treatment of cancer and infectious diseases. The binding affinity and kinetics of a bispecific molecule for both target and T cell CD3 have substantial effects on potency and specificity, but the rules governing these relationships are not fully understood. Using ImmTAC (Immune mobilizing monoclonal TCRs Against Cancer) molecules as a model, we explored the impact of altering affinity for target and CD3 on the potency and specificity of the re-directed T cell response. This class of bispecifics, exemplified by tebentafusp which has recently shown survival benefit in a randomized phase 3 clinical trial1, bind specific target peptides presented by human leukocyte antigen (HLA) on the cell surface via an affinity-enhanced T cell receptor and can redirect T cell activation with an anti-CD3 effector moiety. The data reveal that combining a strong affinity TCR with an intermediate affinity anti-CD3 results in optimal T cell activation, while strong affinity of both targeting and effector domains significantly reduces efficacy. Moreover, by optimising the affinity of both parts of the molecule, it is possible to improve the therapeutic window. These results could be effectively modelled based on kinetic proof-reading with limited signalling. This model explained the experimental observation that strong binding at both ends of the molecules leads to reduced activity, through very stable target-bispecific-effector complexes leading to CD3 entering a non-signalling dark-state. These findings have important implications for the design of anti-CD3 based bispecifics with optimal biophysical parameters for both activity and specificity.

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Staggered starts in the race to T cell activation

Cited by 7 publications

References 143 publications

Time required for commitment to T cell proliferation depends on TCR affinity and cytokine response

Time required for commitment to T cell proliferation depends on TCR affinity and cytokine response

Divide and Conquer: Phenotypic and Temporal Heterogeneity Within CD8+ T Cell Responses

Tuning the potency and therapeutic window of ImmTAC molecules by affinity modulation

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