A central role for Notch in effector CD8+ T cell differentiation

Backer, Ronald A.; Helbig, Christina; Gentek, Rebecca; Kent, Andrew; Laidlaw, Brian J.; Dominguez, Claudia X.; Souza, Yevan S de; Trierum, Stella E. van; Beek, Ruud van; Rimmelzwaan, Guus F.; Brinke, Anja ten; Willemsen, A.M.; Kampen, Antoine H. C. van; Kaech, Susan M.; Blander, J. Magarian; Gisbergen, Klaas P. J. M. van; Amsen, Derk

doi:10.1038/ni.3027

Cited by 100 publications

(95 citation statements)

References 60 publications

(99 reference statements)

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“…Although we did not observe a significant decrease in the level of T-bet protein, the transcription level of Tbx21 was reduced in Notch D/D effectors obtained following Listeria infection, but not following DC vaccination. The reduction in Tbx21 transcription that we observe following Lm-OVA infection is in agreement with the very recent report of Backer et al (50) using an Influenza infection model. Therefore, this suggests that the Notch signaling pathway may contribute to the regulation of Tbx21 transcription in models with high inflammation.…”

Section: Discussionsupporting

confidence: 82%

“…A possible mechanism by which Notch regulation of CD25 expression could affect SLEC differentiation is via modulation of T cell metabolism, as IL-2 signaling is known to regulate the activity of the Akt/mTOR pathway (52)(53)(54)(55). This possibility is in agreement with the very recent observation of Backer et al (50), who have shown reduced activation of the Akt-mTOR pathway in Notchdeficient CD8 + Te cells.…”

Section: Discussionsupporting

confidence: 81%

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The Notch Signaling Pathway Controls Short-Lived Effector CD8+ T Cell Differentiation but Is Dispensable for Memory Generation

Mathieu

Duval

Daudelin

et al. 2015

The Journal of Immunology

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Following an infection, naive CD8+ T cells expand and differentiate into two main populations of effectors: short-lived effector cells (SLECs) and memory precursor effector cells (MPECs). There is limited understanding of the molecular mechanism and cellular processes governing this cell fate. Notch is a key regulator of cell fate decision relevant in many immunological pathways. In this study, we add to the role of Notch in cell fate decision and demonstrate that the Notch signaling pathway controls the MPEC/SLEC differentiation choice following both Listeria infection and dendritic cell immunization of mice. Although fewer SLECs were generated, Notch deficiency did not alter the rate of memory CD8+ T cell generation. Moreover, we reveal that the Notch signaling pathway plays a context-dependent role for optimal cytokine production by effector CD8+ T cells. Together, our results unravel critical functions for the Notch signaling pathway during effector CD8+ T cell differentiation.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionsupporting

confidence: 81%

The Notch Signaling Pathway Controls Short-Lived Effector CD8+ T Cell Differentiation but Is Dispensable for Memory Generation

Mathieu

Duval

Daudelin

et al. 2015

The Journal of Immunology

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“…Notch regulates the genetic programs important for effector differentiation independently of cytokine signals. 16,[55][56][57] Notch binds to the regulatory regions of genes encoding transcription factors (eg, Tbx21, Rorc, and Gata3) and cytokines (eg, Ifng, Il17, and Il4), 50,[55][56][57] thereby amplifying signals for Th differentiation. 55 We found that Dll4 hi DC-derived Dll4 was critical for activating Notch signaling in alloreactive T cells.…”

Section: Discussionmentioning

confidence: 99%

“…[12][13][14][15][16] Notch receptors interact with Notch ligands of the d-like and Jagged families, [17][18][19] triggering the release of intracellular Notch (ICN) that activates Notch target genes. [17][18][19] Inhibiting pan-Notch signaling in donor T cells reduced their production of interferon g (IFN-g) and interleukin-17 (IL-17).…”

Section: • Establishing a Novel Dll4mentioning

confidence: 99%

Programming of donor T cells using allogeneic δ-like ligand 4–positive dendritic cells to reduce GVHD in mice

Mochizuki

Meng

Mochizuki

et al. 2016

Blood

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Alloreactive T cells play a critical role in eliminating hematopoietic malignant cells but are also the mediators of graft-versus-host disease (GVHD), a major complication that subverts the success of allogeneic hematopoietic stem cell transplantation (HSCT). However, induction of alloreactive T cells does not necessarily lead to GVHD. Here we report the development of a cellular programming approach to render alloreactive T cells incapable of causing severe GVHD in both major histocompatibility complex (MHC)-mismatched and MHC-identical but minor histocompatibility antigen-mismatched mouse models. We

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“…Growing evidence indicates that miRNAs are also involved in regulating the Notch and Wnt/β-catenin signaling pathways, which play an important role in the differentiation of memory T cells [73,74]. A recent study indicated that Notch signaling redirects differentiation from memory precursor-like activated CD8 + T cells to stem cell memory T-like cells, which have a long-lived and self-renewing potential [75].…”

Section: Mirna Regulation Of Signaling Pathwaysmentioning

confidence: 99%

Regulation of Memory CD8+ T Cell Differentiation by MicroRNAs

Zhang

et al. 2018

Cell Physiol Biochem

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MicroRNAs (miRNAs) have emerged as crucial regulators of T lymphocyte survival, differentiation and function, all of which are key factors impacting the outcome of adoptive T cell-based immunotherapy. It has become increasingly clear that the adoptive transfer of memory CD8⁺ T cell subsets is highly correlated with objective clinical responses for patients with advanced cancer. However, it is unclear how to improve the long-term persistence of transferred CD8⁺ T cells using miRNAs. Here, we highlight the current advances in our understanding of the role of miRNAs in regulating the differentiation of memory CD8⁺ T cells. We specifically discuss the effect of miRNAs on key transcription factors, immune checkpoints and signal pathways, which contribute to the differentiation of effector and memory T cell subsets. Ultimately, miRNAs may be easily integrated into existing T cell receptor (TCR) and chimeric antigen receptor (CAR) platforms to promote adoptive T cell therapy with multiple advantages. Thus, combining T cell-based therapy with miRNAs could be considered a promising and robust strategy for cancer treatment.

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A central role for Notch in effector CD8+ T cell differentiation

Cited by 100 publications

References 60 publications

The Notch Signaling Pathway Controls Short-Lived Effector CD8+ T Cell Differentiation but Is Dispensable for Memory Generation

The Notch Signaling Pathway Controls Short-Lived Effector CD8+ T Cell Differentiation but Is Dispensable for Memory Generation

Programming of donor T cells using allogeneic δ-like ligand 4–positive dendritic cells to reduce GVHD in mice

Regulation of Memory CD8+ T Cell Differentiation by MicroRNAs

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