Functional heterogeneity and adaptation of naive T cells in response to tonic TCR signals

Eggert, Joel; Au-Yeung, Byron B

doi:10.1016/j.coi.2021.09.007

Cited by 11 publications

(10 citation statements)

References 64 publications

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“…Such tuning can result in sensitization of signaling modules rather than desensitization. Thus, the ongoing integration of TCR-mediated signals and accessory signals in the interactive milieu could prepare lymphocytes to respond more efficiently, rather than less, upon activation by a cognate pathogen ( 26 , 48 , 52 ). Conversely, during strong, chronic antigenic exposure, negatively tuned CD8+ T cells adaptively differentiate and acquire an “exhausted” phenotype, preventing immunopathology ( 53 ).…”

Section: Acute and Chronic Infection And The Significance Of Subthres...mentioning

confidence: 99%

“…Yet, recent studies demonstrated that even the progressive differentiation of lymphocytes into effector memory cells following activation and clonal expansion is adaptive in nature [reviewed, ( 77 – 80 )]. While acute infection elicits a relatively stereotypic sequence of division and maturation events, the actual biochemical pathways that determine gene expression patterns are varied, depending not only on the developmental states of the responding lymphocytes and on their tuning states and acquired features – that is, in our terms, on their previous experience in response to subthreshold perturbations ( 26 , 52 , 81 ), – but also on post-activation experience. Dynamic variation of signaling pathways and chromatin modification orchestrate the establishment and maintenance of distinct states of T-cell fate determination and functional commitment, including metabolic, localization, and trafficking properties ( 78 , 80 ).…”

Section: Effector Memory T Cells Learn As Wellmentioning

confidence: 99%

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An integrative systems biology view of host-pathogen interactions: The regulation of immunity and homeostasis is concomitant, flexible, and smart

2023

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The systemic bio-organization of humans and other mammals is essentially “preprogrammed”, and the basic interacting units, the cells, can be crudely mapped into discrete sets of developmental lineages and maturation states. Over several decades, however, and focusing on the immune system, we and others invoked evidence – now overwhelming – suggesting dynamic acquisition of cellular properties and functions, through tuning, re-networking, chromatin remodeling, and adaptive differentiation. The genetically encoded “algorithms” that govern the integration of signals and the computation of new states are not fully understood but are believed to be “smart”, designed to enable the cells and the system to discriminate meaningful perturbations from each other and from “noise”. Cellular sensory and response properties are shaped in part by recurring temporal patterns, or features, of the signaling environment. We compared this phenomenon to associative brain learning. We proposed that interactive cell learning is subject to selective pressures geared to performance, allowing the response of immune cells to injury or infection to be progressively coordinated with that of other cell types across tissues and organs. This in turn is comparable to supervised brain learning. Guided by feedback from both the tissue itself and the neural system, resident or recruited antigen-specific and innate immune cells can eradicate a pathogen while simultaneously sustaining functional homeostasis. As informative memories of immune responses are imprinted both systemically and within the targeted tissues, it is desirable to enhance tissue preparedness by incorporating attenuated-pathogen vaccines and informed choice of tissue-centered immunomodulators in vaccination schemes. Fortunately, much of the “training” that a living system requires to survive and function in the face of disturbances from outside or within is already incorporated into its design, so it does not need to deep-learn how to face a new challenge each time from scratch. Instead, the system learns from experience how to efficiently select a built-in strategy, or a combination of those, and can then use tuning to refine its organization and responses. Efforts to identify and therapeutically augment such strategies can take advantage of existing integrative modeling approaches. One recently explored strategy is boosting the flux of uninfected cells into and throughout an infected tissue to rinse and replace the infected cells.

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Section: Acute and Chronic Infection And The Significance Of Subthres...mentioning

confidence: 99%

Section: Effector Memory T Cells Learn As Wellmentioning

confidence: 99%

An integrative systems biology view of host-pathogen interactions: The regulation of immunity and homeostasis is concomitant, flexible, and smart

2023

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“…[45][46][47] In humans, 95% of mature CD4 + and CD8 + T cells express an αβ TCR which harbors relatively low TCR affinity for self-pMHC, termed tonic (or basal) signaling. 48 Notably, TCR signaling is negatively regulated by the surface expression of CD5 molecules. CD5 hi cells show higher expression of lipid rafts which bolster the sensitivity to the TCR stimulation.…”

Section: Cholesterol Metabolism and T Cells Are Close Interlinkedmentioning

confidence: 99%

Cholesterol metabolism in T‐cell aging: Accomplices or victims

Zhu

et al. 2023

The FASEB Journal

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Aging has a significant impact on the function and metabolism of T cells. Cholesterol, the most important sterol in mammals, is known as the “gold of the body” because it maintains membrane fluidity, rigidity, and signal transduction while also serving as a precursor of oxysterols, bile acids, and steroid hormones. Cholesterol homeostasis is primarily controlled by uptake, biosynthesis, efflux, and regulatory mechanisms. Previous studies have suggested that there are reciprocal interactions between cholesterol metabolism and T lymphocytes. Here, we will summarize the most recent advances in the effects of cholesterol and its derivatives on T‐cell aging. We will furthermore discuss interventions that might be used to help older individuals with immune deficiencies or diminishing immune competence.

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“…One of the most extensively studied factors associated with naïve T cell response propensity is tonic signaling from weak interactions with self-pMHC ligands. While a full discussion of this topic has recently been published elsewhere (138), a few key studies, particularly in CD8 + T cells, will be highlighted. Tonic signaling can diversify the antigen-inexperienced T cell population both by driving differentiation of virtual memory cells (139) and by affecting the true naïve population.…”

Section: Origins Of Heterogeneity Among Naïve T Cellsmentioning

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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Functional heterogeneity and adaptation of naive T cells in response to tonic TCR signals

Cited by 11 publications

References 64 publications

An integrative systems biology view of host-pathogen interactions: The regulation of immunity and homeostasis is concomitant, flexible, and smart

An integrative systems biology view of host-pathogen interactions: The regulation of immunity and homeostasis is concomitant, flexible, and smart

Cholesterol metabolism in T‐cell aging: Accomplices or victims

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

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