Staggered starts in the race to T cell activation.
TL;DR: In this paper, a probabilistic model was proposed to tune the response of T lymphocytes to different strengths of stimulation, which allowed activating T cells to achieve a wide range of population responses.
About: This article is published in Trends in Immunology.The article was published on 2021-10-11. It has received 4 citations till now. The article focuses on the topics: T cell & Stimulation.
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TL;DR: 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.
Abstract: 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.
5 citations
TL;DR: Elliot et al. as discussed by the authors exploited accelerated in vivo adaptive tolerance in the face of strong TCR signaling to attenuate subsequent antigen responses through adaptive tolerance, thus averting autoimmunity, but potentially also providing refuge to developing cancers.
3 citations
TL;DR: In this paper , the role of TCR-pMHC affinity in regulating the kinetics of CD8+ T cell commitment to proliferation and differentiation is unknown, however, it is shown that the stronger the TCRp-mHC affinity, the shorter the time of T cell-APC co-culture required to commit CD 8+ T cells to proliferation.
Abstract: 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.
2 citations
TL;DR: In this article , the authors explored the impact of altering affinity for target and CD3 on the potency and specificity of the re-directed T cell response using ImmTAC (Immune mobilizing monoclonal TCRs Against Cancer).
Abstract: 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. Graphical abstract
References
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TL;DR: Single-cell “mass cytometry” analyses provide system-wide views of immune signaling in healthy human hematopoiesis, against which drug action and disease can be compared for mechanistic studies and pharmacologic intervention.
Abstract: Flow cytometry is an essential tool for dissecting the functional complexity of hematopoiesis. We used single-cell "mass cytometry" to examine healthy human bone marrow, measuring 34 parameters simultaneously in single cells (binding of 31 antibodies, viability, DNA content, and relative cell size). The signaling behavior of cell subsets spanning a defined hematopoietic hierarchy was monitored with 18 simultaneous markers of functional signaling states perturbed by a set of ex vivo stimuli and inhibitors. The data set allowed for an algorithmically driven assembly of related cell types defined by surface antigen expression, providing a superimposable map of cell signaling responses in combination with drug inhibition. Visualized in this manner, the analysis revealed previously unappreciated instances of both precise signaling responses that were bounded within conventionally defined cell subsets and more continuous phosphorylation responses that crossed cell population boundaries in unexpected manners yet tracked closely with cellular phenotype. Collectively, such single-cell analyses provide system-wide views of immune signaling in healthy human hematopoiesis, against which drug action and disease can be compared for mechanistic studies and pharmacologic intervention.
2,147 citations