Quorum Regulation via Nested Antagonistic Feedback Circuits Mediated by the Receptors CD28 and CTLA-4 Confers Robustness to T Cell Population Dynamics

Zenke, Simon; Palm, Margriet; Braun, Julia M.; Gavrilov, Alina; Meiser, Philippa; Böttcher, Jan; Beyersdorf, Niklas; Ehl, Stephan; Gérard, Audrey; Lämmermann, Tim; Schumacher, Ton N.; Beltman, Joost B.; Rohr, Jan

doi:10.1016/j.immuni.2020.01.018

Cited by 63 publications

(71 citation statements)

References 51 publications

(74 reference statements)

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“…In vivo, activated CD4 + T cells clustering around DCs cause CD8 + T cell accumulation through CCL3/CCL4-CCR5 binding, which enhances CD8 + T cell/DC contact formation [65], highlighting the crucial role of chemokines in enabling activating T cells to find each other and create the niche that serves as a platform for subsequent T-T communication. While this mechanism relies on another cellular intermediate, it is conceivable that T cells also directly attract each other via other chemokines, as they up-regulate multiple chemokine/chemokine receptor pairs [15].…”

Section: B-chemokinesmentioning

confidence: 99%

“…Various studies have demonstrated that activated T cells are able to find each other [65,94,95]. Multiple chemokine/receptor pairs are upregulated by T cells following priming [15], suggesting that primed T cells can attract each other. Similarly, antigen-specific CD8 + T cells favour the priming of naive CD8 + T cells, by promoting the CCR5-dependent recruitment of polyclonal CD8 + T cells to mature dendritic cells [94], resulting in the amplification of priming.…”

Section: Regulation Of T Cell Primingmentioning

confidence: 99%

“…Antigen-specific CD8 + T cells similarly rely on autocrine IL-2 production by neighbouring activating CD8 + T cells as the main source of this critical cue, rather than depending on paracrine IL-2 signals from CD4 + T cells or DCs [31,113]. Recently, a paper by Zenke et al demonstrated that nested antagonistic IL-2 and CD80/86-CTLA-4-mediated feedback mechanisms function to promote or inhibit CD8 + T cell expansion, based on cellular density [15]. ICAM-1-mediated cell clustering facilitates T cell population-intrinsic mechanisms, which enable T cells to collectively self-regulate their proliferation and apoptosis during their expansion.…”

Section: Sensing Population Size During Immune Responsesmentioning

confidence: 99%

“…T-T interactions have also been shown in vitro to trigger CD4 + T cell activation, proliferation, and differentiation [126], and in vivo to induce the generation of CD4 + T cells with a regulatory phenotype, characterised by the production of IL-4, IL-10 and TGF-β [85]. In CD8 + T cells, LFA-1/ICAM-1 dependent clustering promotes their expansion [15,19,23].…”

Section: Regulation Of T Cell Differentiationmentioning

confidence: 99%

“…Coordination between T cells on a system-wide level relies on efficient and constant T-T communication. While the characterisation of T-T communication is still in its infancy, a list of potential mediators between CD8 + T cells has been recently identified through a bioinformatics approach, based on the expression of receptor-ligand pairs in T cells, their upregulation upon T cell activation, and their co-regulation in multiple infection models [15]. Overall, it is believed T cells produce and secrete soluble factors into the local environment, which enables them to translate and coordinate local interactions into tissue-wide global behaviour.…”

Section: Introductionmentioning

confidence: 99%

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Modes of Communication between T Cells and Relevance for Immune Responses

Uhl

Gérard

2020

IJMS

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T cells are essential mediators of the adaptive immune system, which constantly patrol the body in search for invading pathogens. During an infection, T cells that recognise the pathogen are recruited, expand and differentiate into subtypes tailored to the infection. In addition, they differentiate into subsets required for short and long-term control of the pathogen, i.e., effector or memory. T cells have a remarkable degree of plasticity and heterogeneity in their response, however, their overall response to a given infection is consistent and robust. Much research has focused on how individual T cells are activated and programmed. However, in order to achieve a critical level of population-wide reproducibility and robustness, neighbouring cells and surrounding tissues have to provide or amplify relevant signals to tune the overall response accordingly. The characteristics of the immune response—stochastic on the individual cell level, robust on the global level—necessitate coordinated responses on a system-wide level, which facilitates the control of pathogens, while maintaining self-tolerance. This global coordination can only be achieved by constant cellular communication between responding cells, and faults in this intercellular crosstalk can potentially lead to immunopathology or autoimmunity. In this review, we will discuss how T cells mount a global, collective response, by describing the modes of T cell-T cell (T-T) communication they use and highlighting their physiological relevance in programming and controlling the T cell response.

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Section: B-chemokinesmentioning

confidence: 99%

Section: Regulation Of T Cell Primingmentioning

confidence: 99%

Section: Sensing Population Size During Immune Responsesmentioning

confidence: 99%

Section: Regulation Of T Cell Differentiationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Modes of Communication between T Cells and Relevance for Immune Responses

Uhl

Gérard

2020

IJMS

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Zfp36l1 establishes the high‐affinity CD8 T‐cell response by directly linking TCR affinity to cytokine sensing

Petkau,

Mitchell,

Evans

et al. 2023

Eur J Immunol

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How individual T cells compete for and respond to IL‐2 at the molecular level, and, as a consequence, how this shapes population dynamics and the selection of high‐affinity clones is still poorly understood. Here we describe how the RNA binding protein ZFP36L1, acts as a sensor of TCR affinity to promote clonal expansion of high‐affinity CD8 T cells. As part of an incoherent feed‐forward loop, ZFP36L1 has a nonredundant role in suppressing multiple negative regulators of cytokine signaling and mediating a selection mechanism based on competition for IL‐2. We suggest that ZFP36L1 acts as a sensor of antigen affinity and establishes the dominance of high‐affinity T cells by installing a hierarchical response to IL‐2.

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CD8 agonism functionally activates memory T cells and enhances antitumor immunity

Madi

Weisshaar

Buettner

et al. 2022

Intl Journal of Cancer

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Memory CD8+ T cells mature after antigen clearance and ultimately express CD8 protein at levels higher than those detected in effector CD8+ T cells. However, it is not clear whether engagement of CD8 in the absence of antigenic stimulation will result in the functional activation of T cells. Here, we found that CD8 antibody‐mediated activation of memory CD8+ T cells triggered T cell receptor (TCR) downstream signaling, enhanced T cell‐mediated cytotoxicity and promoted effector cytokine production in a glucose‐ and glutamine‐dependent manner. Furthermore, pretreatment of memory CD8+ T cells with an agonistic anti‐CD8 antibody enhanced their tumoricidal activity in vitro and in vivo. From these studies, we conclude that CD8 agonism activates glucose and glutamine metabolism in memory T cells and enhances the efficacy of memory T cell‐based cancer immunotherapy.

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Quorum Regulation via Nested Antagonistic Feedback Circuits Mediated by the Receptors CD28 and CTLA-4 Confers Robustness to T Cell Population Dynamics

Cited by 63 publications

References 51 publications

Modes of Communication between T Cells and Relevance for Immune Responses

Modes of Communication between T Cells and Relevance for Immune Responses

Zfp36l1 establishes the high‐affinity CD8 T‐cell response by directly linking TCR affinity to cytokine sensing

CD8 agonism functionally activates memory T cells and enhances antitumor immunity

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