Real-time tracking of cell cycle progression during CD8+ effector and memory T-cell differentiation

Kinjyo, Ichiko; Qin, Jim; Tan, Sioh Yang; Wellard, Cameron; Mrass, Paulus; Ritchie, William; Doi, Atsushi; Cavanagh, Lois L.; Tomura, Michio; Sakaue-Sawano, Asako; Kanagawa, Osami; Miyawaki, Atsushi; Hodgkin, Philip D.; Weninger, Wolfgang

doi:10.1038/ncomms7301

Cited by 134 publications

(175 citation statements)

References 56 publications

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“…This is possible if crucial regulators of the biosynthetic and mitotic machinery accumulate in proportion to the sum of all three signals -and are then diluted during each round of division because of a lack of any additional accumulation. This assertion is also supported by the observation that the time taken for later divisions increases [32]. Two recently described transcription factors necessary for CD8 T cell clonal expansion and effector differentiation, BATF and IRF4, have characteristics suitable to enable scaled response in the context described above: (i) gradual accumulation of IRF4 over the first 24-48 h scales according to antigenic dose and strength ex vivo [33,34].…”

Section: Scaled Accumulation Of Crucial Mediators By Temporal Integramentioning

confidence: 57%

What Scales the T Cell Response?

Mayya

Dustin

2016

Trends in Immunology

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T cells are known to scale their clonal expansion and effector cytokine response according to the dose and strength of antigenic signal so as to balance their role of affecting protection with the intertwined and immunologically driven tissue damage. How T cells achieve this is now beginning to be understood. We underscore temporal integration of digital T cell receptor (TCR) signaling as the basis for achieving scaled response by means of accumulating crucial mediators over time. We also discuss the role of temporally integrated crosstalk between TCR and IL2 signaling in mediating a scaled, coherent, collective response by T cells. Finally, we highlight numerous known and putative regulatory interactions in the transcriptional program that are expected to quantitatively scale the T cell response, and also offer new mechanisms to hitherto unexplained observations.

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Section: Scaled Accumulation Of Crucial Mediators By Temporal Integramentioning

confidence: 57%

What Scales the T Cell Response?

Mayya

Dustin

2016

Trends in Immunology

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“…The most obvious effect of PD-L1 mAb is a prominent increase in the number of CD62L − CD44 + CXCR3 + CD8 + T cells in DLNs. This cellular subset, called "effectormemory," contains heterogeneous activated T cells ready to execute their effector functions (58,59). However, the surgical removal of tumors is often accompanied by the excision of DLNs, which could reduce the antitumor activity of the immune system.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity

Chamoto

Chowdhury

Kumar

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

312

275

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Although immunotherapy by PD-1 blockade has dramatically improved the survival rate of cancer patients, further improvement in efficacy is required to reduce the fraction of less sensitive patients. In mouse models of PD-1 blockade therapy, we found that tumor-reactive cytotoxic T lymphocytes (CTLs) in draining lymph nodes (DLNs) carry increased mitochondrial mass and more reactive oxygen species (ROS). We show that ROS generation by ROS precursors or indirectly by mitochondrial uncouplers synergized the tumoricidal activity of PD-1 blockade by expansion of effector/ memory CTLs in DLNs and within the tumor. These CTLs carry not only the activation of mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) but also an increment of their downstream transcription factors such as PPAR-gamma coactivator 1α (PGC-1α) and T-bet. Furthermore, direct activators of mTOR, AMPK, or PGC-1α also synergized the PD-1 blockade therapy whereas none of above-mentioned chemicals alone had any effects on tumor growth. These findings will pave a way to developing novel combinatorial therapies with PD-1 blockade.PD-1 | cancer immunotherapy | mitochondria | immune metabolism | PGC-1α

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“…However, T cell expansion and differentiation has been shown to be a tightly coupled processes initiated by signaling via the TCR, co-stimulatory molecules and cytokine receptors. 6,10,11 These joined signals activate the PI3K/AKT/mTOR-pathway that has been shown to play a pivotal role in regulating CD8 + T cell differentiation and memory formation. 12,13 Interestingly however, interference of PI3K/AKT signaling does not severely impair the proliferation of murine CD8 + T cells.…”

Section: Introductionmentioning

confidence: 99%

Ex vivo AKT-inhibition facilitates generation of polyfunctional stem cell memory-like CD8⁺ T cells for adoptive immunotherapy

Mousset

Hobo

et al. 2018

OncoImmunology

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Adoptive T cell therapy has shown clinical potential for patients with cancer, though effective treatment is dependent on longevity and potency of the exploited tumor-reactive T cells. Previously, we showed that ex vivo inhibition of AKT using the research compound Akt-inhibitor VIII retained differentiation and improved functionality of minor histocompatibility antigen (MiHA)-specific CD8+ T cells. Here, we compared a panel of clinically applicable AKT-inhibitors with an allosteric or adenosine triphosphate-competitive mode of action. We analyzed phenotype, functionality, metabolism and transcriptome of AKT-inhibited CD8+ T cells using different T cell activation models. Most inhibitors facilitated T cell expansion while preserving an early memory phenotype, reflected by maintenance of CD62L, CCR7 and CXCR4 expression. Moreover, transcriptome profiling revealed that AKT-inhibited CD8+ T cells clustered closely to naturally occurring stem cell-memory CD8+ T cells, while control T cells resembled effector-memory T cells. Interestingly, AKT-inhibited CD8+ T cells showed enrichment of hypoxia-associated genes, which was consistent with enhanced glycolytic function. Notably, AKT-inhibition during MiHA-specific CD8+ T cell priming uncoupled preservation of early memory differentiation from ex vivo expansion. Furthermore, AKT-inhibited MiHA-specific CD8+ T cells showed increased polyfunctionality with co-secretion of IFN-γ and IL-2 upon antigen recall. Together, these data demonstrate that AKT-inhibitors with different modality of action promote the ex vivo generation of stem cell memory-like CD8+ T cells with a unique metabolic profile and retained polyfunctionality. Akt-inhibitor VIII and GDC-0068 outperformed other inhibitors, and are therefore promising candidates for ex vivo generation of superior tumor-reactive T cells for adoptive immunotherapy in cancer patients.

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Real-time tracking of cell cycle progression during CD8+ effector and memory T-cell differentiation

Cited by 134 publications

References 56 publications

What Scales the T Cell Response?

What Scales the T Cell Response?

Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity

Ex vivo AKT-inhibition facilitates generation of polyfunctional stem cell memory-like CD8⁺ T cells for adoptive immunotherapy

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Real-time tracking of cell cycle progression during CD8+ effector and memory T-cell differentiation

Cited by 134 publications

References 56 publications

What Scales the T Cell Response?

What Scales the T Cell Response?

Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity

Ex vivo AKT-inhibition facilitates generation of polyfunctional stem cell memory-like CD8+ T cells for adoptive immunotherapy

Contact Info

Product

Resources

About

Ex vivo AKT-inhibition facilitates generation of polyfunctional stem cell memory-like CD8⁺ T cells for adoptive immunotherapy