Asymmetric Cell Division of T Cells upon Antigen Presentation Uses Multiple Conserved Mechanisms

Oliaro, Jane; Ham, Vanessa van; Sacirbegovic, Faruk; Pasam, Anupama; Bomzon, Zéev; Pham, Kim; Ludford-Menting, Mandy; Waterhouse, Nigel J.; Bots, Michael; Hawkins, Edwin D.; Watt, Sally V.; Cluse, Leonie A.; Clarke, Chris J P; Izon, David J.; Chang, John T.; Thompson, Natalie; Gu, Miṅ; Johnstone, Ricky W.; Smyth, Mark J.; Humbert, Patrick O.; Reiner, Steven L.; Russell, Sarah M.

doi:10.4049/jimmunol.0903627

Cited by 116 publications

(181 citation statements)

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“…Third, through physical separation of paired daughter T cells, we provided evidence that T cell diversification can be initiated in the context of the first T cell division. Differences in paired daughter cells may originate from an asymmetric cell division, as recently proposed (15)(16)(17)(18), or alternatively from random events occurring just after the cell division, such as variability in exposure to cytokines. We focused our analysis on two important markers, CD25 and CD62L, whose expression levels regulate T cell functional responses.…”

Section: Discussionmentioning

confidence: 99%

“…Stochastic events occurring after the first T cell division, such as Ag re-encounter (14) or exposure to a distinct cytokine milieu, may account for intraclonal diversification. In addition, it has recently been proposed that the first T cell division occurs in an asymmetric fashion (15)(16)(17), a process that could involve asymmetric proteasome segregation (18) and have the potential to generate phenotypic and functional diversity within a T cell progeny.…”

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confidence: 99%

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Phenotypic CD8+ T Cell Diversification Occurs before, during, and after the First T Cell Division

Lemaı̂tre

Moreau

Vedele

et al. 2013

The Journal of Immunology

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International audienceEffector T cell responses rely on a phenotypically and functionally heterogeneous population of cells. Whether this diversity is programmed before clonal expansion or in later phases as a result of stochastic events or asymmetric cell division is not fully understood. In this study, we first took advantage of a sensitive in vitro assay to analyze the composition of single CD8(+) T cell progenies. Heterogeneity was predominantly observed between progenies of distinct clones, but could also be detected within individual progenies. Furthermore, by physically isolating daughter cells of the first T cell division, we showed that differences in paired daughter cell progenies contributed to intraclonal diversification. Finally, we developed an in vivo limiting dilution assay to compare individual T cell progenies following immunization. We provided evidence for simultaneous intraclonal and interclonal diversification in vivo. Our results support the idea that T cell diversification is a continuous process, initiated before clonal expansion and amplified during the first and subsequent cell divisions

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Phenotypic CD8+ T Cell Diversification Occurs before, during, and after the First T Cell Division

Lemaı̂tre

Moreau

Vedele

et al. 2013

The Journal of Immunology

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“…This alignment is regulated by the polarity complexes Dlg and Partner of Inscuteable (Pins) [12]. Scribble and aPKC are asymmetrically distributed in mitotic T cells responding to Listeria infection [80]. aPKC and Par3 polarize to the distal side of the cell in early mitotic T cells and maintain this asymmetry during late mitosis.…”

Section: Asymmetric Cell Division: the Ultimate Polarizationmentioning

confidence: 99%

“…CD3 and IL2Rα are similarly recruited in CD8 memory cells [100]. The polarity proteins known as partitioning defective (Par) proteins consist of the Par3-Par6-atypical PKC (aPKC) and Discs large (Dlg)-Scribble-Lethal giant larvae (Lgl) polarity complexes and are differentially distributed during asymmetric cell division, as is Numb, an endocytic adaptor that can also help to regulate polarity [80]. Indeed, several transcriptional regulators undergo asymmetric segregation in lymphocytes.…”

Section: Mitochondria Ros and Nuclear Activationmentioning

confidence: 99%

Immune synapse: conductor of orchestrated organelle movement

Martín-Cófreces¹,

Baixauli²,

Sánchez-Madrid³

2014

Trends in Cell Biology

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SummaryTo ensure proper cell function, intracellular organelles are not randomly distributed within the cell, but polarized and highly constrained by the cytoskeleton and associated adaptor proteins. This relationship between distribution and function was originally found in neurons and epithelial cells; however, recent evidence suggests that it is a more general phenomenon that occurs in many highly specialized cells including the immune T cells. Recent studies reveal that the orchestrated redistribution of organelles is dependent on antigen specific activation and immune-synapse formation of T cells. This review highlights the functional implications of organelle polarization in early T cell activation and examines recent findings on how the immune synapse sets the rhythm of organelle motion and the spread of the activation signal to the nucleus. KeywordsImmune synapse; microcluster; signalosome; mitochondria; vesicle; microtubule Overview of the immune synapseT cell activation starts with an initial wave of signalling that depends on the activation of surface receptors, but subsequent propagation of the signal appears to depend on intracellular compartments, in a sequence driven by the actin and tubulin cytoskeletons [1]. The study of neural synapses highlighted the importance of cell polarity and the specific localization of organelles and clusters of receptors at the pre-and post-synaptic terminals. Despite its transient nature, recent evidence shows that the immune synapse (IS) shares these same neuronal features.The IS is the interface between a T lymphocyte and an antigen presenting cell (APC). During the formation and stabilization of the IS, membrane microdomains and the cytoskeleton reorganize and promote the segregation of membrane and intracellular signaling proteins within the T cell, such as the T cell receptor (TCR), integrins, tyrosine Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts kinases and scaffold proteins such as Linker for activation of T cells (LAT) (Figure 1 and Glossary). The TCR and associated molecules (TCR signalosomes) form microclusters that move to congregate in the central area (central supramolecular activation cluster; cSMAC) of the IS, whereas adhesion receptors such as integrins reorganize in a surrounding external ring called the peripheral or pSMAC ( Figure 2) [2]. In addition, phosphorylation and dephosphorylation, protein-protein interactions and degradation of important molecules such as the TCR-accompanying CD3 complex, tyrosine kinases, phosphatases and adaptor molecules also control receptor activation [3,4]. The polarization of several organelles occurs during T cell stimulation with important roles, such as the centrosome, Golgi apparatus, mitochondria, endoplasmic reticulum and the multivesicular bodies (MVB) [5][6][7][8][9][10]. These rearrangements at the IS promote the activation of signaling pathways that propagate to the nucleus. Signals activating nuclear transcription factors in combination with polarity proteins, such as partit...

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“…The immunological synapse has been extensively studied as a site of clustered signaling molecules, and can be considered as a marker of the polarized T cell and a mechanism for asymmetric division regulation. Recent studies showed that asymmetric cell division is not observed either during non antigen-dependent activation or the second and subsequent cell divisions following antigen stimulation, and that the polarity cue for asymmetric cell division requires the contact with antigen-presenting cells (Chang et al 2007;Oliaro et al 2010; Fig. 3).…”

Section: Asymmetric Division In the Immune Systemmentioning

confidence: 99%