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

Mathieu, Mélissa; Duval, Frédéric; Daudelin, Jean-François; Labrecque, Nathalie

doi:10.4049/jimmunol.1402837

Cited by 40 publications

(47 citation statements)

References 62 publications

(103 reference statements)

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“…DLL1 and 4 induced development of Th1 cells and effector memory CD8 + T-cells (15,25–29), whereas Jagged1 and 2 skewed T-cells into Th2, Treg, and anergic CD8 + T-populations (16,30–33). In agreement with the proposed immune inhibitory role of Jagged, we found that anti-Jagged overcame tumor-T-cell suppression through the induction of potentially immunogenic MDSC-LC.…”

Section: Discussionmentioning

confidence: 99%

Anti-Jagged Immunotherapy Inhibits MDSCs and Overcomes Tumor-Induced Tolerance

et al. 2017

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Myeloid-derived suppressor cells (MDSCs) are a major obstacle to promising forms of cancer immunotherapy, but tools to broadly limit their immunoregulatory effects remain lacking. In this study, we assessed the therapeutic effect of the humanized anti-Jagged1/2 blocking antibody CTX014 on MDSC-mediated T cell suppression in tumor-bearing mice. CTX014 decreased tumor growth, impacted the accumulation and tolerogenic activity of MDSCs in tumors, and inhibited the expression of immunosuppressive factors arginase I and iNOS. Consequently, anti-Jagged therapy overcame tumor-induced T cell tolerance, increased the infiltration of reactive CD8+ T-cells into tumors, and enhanced the efficacy of T cell-based immunotherapy. Depletion of MDSC-like cells restored tumor growth in mice treated with anti-Jagged, whereas co-injection of MDSC-like cells from anti-Jagged-treated mice with cancer cells delayed tumor growth. Jagged1/2 was induced in MDSCs by tumor-derived factors via NFkB-p65 signaling, and conditional deletion of NFkB-p65 blocked MDSC function. Collectively, our results offer a preclinical proof of concept for the use of anti-Jagged1/2 to reprogram MDSC-mediated T cell suppression in tumors, with implications to broadly improve the efficacy of cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Anti-Jagged Immunotherapy Inhibits MDSCs and Overcomes Tumor-Induced Tolerance

et al. 2017

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“…This was shown to be due to the growth effects of IL2 via PI3K signaling that triggers entry into the cell cycle ( Figure 1C). Additional crucial nodes of integration can be gleaned from recently reported studies: (i) Notch1 is activated by T cell signaling in cis, and additional Notch1/2 expression is triggered by IL2 signaling [26,53]. (ii) Further, TCR signaling induces digital expression of Myc, which is subsequently scaled by the level of IL2 signaling [54].…”

Section: Crosstalk With Il-2 Signaling For Collective Scalingmentioning

confidence: 98%

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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“…27,28 In addition, immunologists have pursued investigations into Notch’s role in multiple aspects of adaptive immunity. Thus, a multifaceted impact of Notch signaling on adaptive immunity has surfaced over the past decade, including identification of its enabling role in many arms of Th polarization (including Th1, 29–33,34 Th2, 30,35–39 Th9, 40 and Th17 41,42 ); its effects in terminal effector vs. memory precursor CD8 + T cell differentiation 43–46 ; its effects on regulatory T cell function 47 ; and its synergy with B cell receptor signaling to promote class switching and terminal B cell differentiation and antibody production. 48–50 How Notch mediates such a broad range of immune effects is progressively being elucidated.…”

Section: Notch Signaling In Adaptive Immunitymentioning

confidence: 99%

“…In infectious disease models (Listeria monocytogenes, Influenza), Notch activity was critical to ensure short-lived effector CD8 + T cell differentiation, in part due to direct regulation of Il2ra expression. 45,46 Upon Notch blockade, the acquisition of effector molecules (IFN-γ, Granzyme B, and Perforin) and the ultimate functional impact was variably affected in different models. 45,46 Data on the role of Notch signaling in CD8 + memory responses are more limited, however Notch appeared to favor effector CD8 + T cell responses over memory formation.…”

Section: Notch Signaling In Adaptive Immunitymentioning

confidence: 99%

Notch Signaling and Alloreactivity

Radojčić

Maillard

2016

Transplantation

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Solid organ and allogeneic hematopoietic cell transplantation have become standard therapeutic interventions that save patient lives and improve quality of life. Our enhanced understanding of transplantation immunobiology has refined clinical management and improved outcomes. However, organ rejection and graft-versus-host disease remain major obstacles to the broader successful application of these therapeutic procedures. Notch signaling regulates multiple aspects of adaptive and innate immunity. Preclinical studies identified Notch signaling as a promising target in autoimmune diseases, as well as after allogeneic hematopoietic cell and solid organ transplantation. Notch was found to be a central regulator of alloreactivity across clinically relevant models of transplantation. Notch inhibition in T cells prevented graft-versus-host disease and organ rejection, establishing organ tolerance by skewing CD4+ T helper polarization away from a proinflammatory response towards suppressive regulatory T cells. Notch ligand blockade also dampened alloantibody deposition and prevented chronic rejection through humoral mechanisms. Toxicities of systemic Notch blockade were observed with γ-secretase inhibitors in preclinical and early clinical trials across different indications, but they did not arise upon preclinical targeting of Delta-like Notch ligands, a strategy sufficient to confer full benefits of Notch ablation in T cell alloimmunity. As multiple clinical grade reagents have been developed to target individual Notch ligands and receptors, the benefits of Notch blockade in transplantation are calling for translation of preclinical findings into human transplantation medicine.

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

Cited by 40 publications

References 62 publications

Anti-Jagged Immunotherapy Inhibits MDSCs and Overcomes Tumor-Induced Tolerance

Anti-Jagged Immunotherapy Inhibits MDSCs and Overcomes Tumor-Induced Tolerance

What Scales the T Cell Response?

Notch Signaling and Alloreactivity

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