Notch controls generation and function of human effector CD8+ T cells

Kuijk, Loes M.; Verstege, Marleen I.; Rekers, Niels V.; Bruijns, Sven C. M.; Hooijberg, Erik; Roep, Bart O.; Gruijl, Tanja D. de; Kooyk, Yvette van; Unger, Wendy W. J.

doi:10.1182/blood-2012-07-442962

Cited by 46 publications

(38 citation statements)

References 37 publications

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“…Furthermore, we found that expression of N1IC in antigen-specific CD8 + T cells promoted effector responses through amplification of canonical and non-canonical Notch pathways and rendered T cells resistant to tumor-induced tolerance. A similar promotion of T-cell cytotoxicity by Notch signaling was recently confirmed in human CD8 + T cells (32). In addition, signaling through Notch-2 promoted cytotoxic activity of CD8 + T cells (28), suggesting a similar effect of Notch-1 and -2 in CD8 + T-cell effector responses.…”

Section: Discussionsupporting

confidence: 73%

“…Moreover, Jagged-1 expression suppressed collagen-induced arthritis by providing negative signals in CD8 + T cells (29). Interestingly, treatment of tumor-bearing mice with agonistic antibodies against Notch-2 or DLL1- or DLL4-Fc fusion proteins led to antitumor responses (30-32), suggesting the potential therapeutic effect of promoting Notch signaling in cancer. However, these therapeutic approaches were systemic and did not specifically target T cells.…”

Section: Introductionmentioning

confidence: 99%

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Rescue of Notch-1 Signaling in Antigen-Specific CD8+ T Cells Overcomes Tumor-Induced T-cell Suppression and Enhances Immunotherapy in Cancer

Sierra¹,

Thevenot²,

Raber³

et al. 2014

Cancer Immunology Research

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An impaired antitumor immunity is found in patients with cancer and represents a major obstacle in the successful development of different forms of immunotherapy. Signaling through Notch receptors regulates the differentiation and function of many cell types, including immune cells. However, the effect of Notch in CD8+ T-cell responses in tumors remains unclear. Thus, we aimed to determine the role of Notch signaling in CD8+ T cells in the induction of tumor-induced suppression. Our results using conditional knockout mice show that Notch-1 and -2 were critical for the proliferation and IFMγ production of activated CD8+ T cells and were significantly decreased in tumor-infiltrating T cells. Conditional transgenic expression of Notch-1 intracellular domain (N1IC) in antigen-specific CD8+ T cells did not affect activation or proliferation of CD8+ T cells, but induced a central memory phenotype and increased cytotoxicity effects and granzyme B levels. Consequently, a higher antitumor response and resistance to tumor-induced tolerance were found after adoptive transfer of N1IC-transgenic CD8+ T cells into tumor-bearing mice. Additional results showed that myeloid-derived suppressor cells (MDSC) blocked the expression of Notch-1 and -2 in T cells through nitric oxide-dependent mechanisms. Interestingly, N1IC overexpression rendered CD8+ T cells resistant to the tolerogenic effect induced by MDSC in vivo. Altogether, the results suggest the key role of Notch in the suppression of CD8+ T-cell responses in tumors and the therapeutic potential of N1IC in antigen-specific CD8+ T cells to reverse T-cell suppression and increase the efficacy of T cell-based immunotherapies in cancer.

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Section: Discussionsupporting

confidence: 73%

Section: Introductionmentioning

confidence: 99%

Rescue of Notch-1 Signaling in Antigen-Specific CD8+ T Cells Overcomes Tumor-Induced T-cell Suppression and Enhances Immunotherapy in Cancer

Sierra¹,

Thevenot²,

Raber³

et al. 2014

Cancer Immunology Research

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“…+ T-cell immune responses (21,22) and cytokine/chemokine expression (23). The regulation of Notch1 and Tbx21 by EGR2 thus helps to explain the importance of EGR2 for a normal immune response to influenza.…”

Section: Discussionmentioning

confidence: 99%

EGR2 is critical for peripheral naïve T-cell differentiation and the T-cell response to influenza

Kwon

West

et al. 2014

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

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Early growth response 2 (EGR2) transcription factor negatively regulates T-cell activation, in contrast to the positive regulation of this process by EGR1. Here, we unexpectedly found that EGR2 promotes peripheral naïve T-cell differentiation, with delayed T-cell receptor-induced proliferation in naïve T cells from Egr2 conditional knockout (CKO) mice and decreased production of IFN-γ, IL-4, IL-9, and IL-17A in cells subjected to T-helper differentiation. Moreover, genes that promote T-cell activation, including Tbx21 and Notch1, had decreased expression in Egr2 CKO T cells and are direct EGR2 target genes. Following influenza infection, Egr2 CKO mice had delayed viral clearance, more weight loss, and more severe pathological changes in the lung than did WT and Egr1 KO mice, with decreased production of effector cytokines, increased infiltration of antigen-specific memory-precursor CD8 + T cells, and lower numbers of lung-resident memory CD8 + T cells. Thus, unexpectedly, EGR2 can function as a positive regulator that is essential for naïve T-cell differentiation and in vivo T-cell responses to a viral infection.-cell differentiation involves developmental checkpoints and the actions of multiple transcription factors, including the early growth response (EGR) factors (1). EGR proteins share highly conserved zinc-finger DNA-binding domains that can bind shared target genes (2). In thymocytes, Egr1, Egr2, and Egr3 are induced by pre-T-cell receptor (TCR) signaling and promote progression through the β-selection checkpoint (2). Egr1 is expressed in T cells and thymocytes and acts as a positive regulator for thymocyte development and T-cell activation (3). Egr2 is critical for hindbrain development and peripheral myelination, with perinatal death in Egr2 KO mice (4), but it also contributes to T-and B-cell development (5). Egr2 and Egr3 are NFAT target genes, and EGR2 induces NFAT-dependent regulation of Fas ligand (6). Egr2 is implicated in the development of T-cell anergy (7,8). In CD2-specific Egr2 conditional knockout (CKO) mice, T cells had normal primary activation but hyperproliferated after prolonged stimulation, and older mice develop a lupus-like syndrome (9), with naïve CD4 + T cells prone to Th1 and particularly Th17 differentiation (10). Moreover, simultaneous deletion of Egr2 and Egr3 results in an autoimmune syndrome with increased activated STAT1 and STAT3 but impaired TCR-induced activation of AP-1 (11).Although studies in vitro and in transgenic mice indicate that EGR2 can negatively regulate T-cell activation and contribute to T-cell anergy, studies of EGR2 in peripheral T-cell differentiation and responses to pathological conditions have been limited. Here, we show that Egr2 CKO naïve CD4 + and CD8 + T cells had delayed proliferation and impaired Th and Tc cell differentiation, implicating EGR2 as a positive regulator. IL-2 was diminished, a finding we confirmed in WT T cells in which EGR2 was reduced by treatment with siRNA. Moreover, after influenza infection, Egr2 CKO mice had greater weight l...

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“…The nature of the Notch receptor involved (Notch 1 or Notch 2) may vary depending on the experimental context. A recent study reported a role for Notch also in the generation and function of human CD8 + T cells, suggesting that its role in this particular subset of T cells is conserved 105 . Collectively, these experiments show an important role for Notch signalling in the differentiation of functional CTLs.…”

Section: Box 2 | Notch and Autoimmune Diseasementioning

confidence: 99%

Regulation of innate and adaptive immunity by Notch

2013

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Notch controls generation and function of human effector CD8+ T cells

Abstract: Key Points Activation-induced Notch signaling is crucial for both generation and effector functions of primary naive CD8 T cells. Notch signaling is needed for expansion and IFNγ release but not for cytolytic activity of established effector CD8 T cells.

Cited by 46 publications

References 37 publications

Rescue of Notch-1 Signaling in Antigen-Specific CD8+ T Cells Overcomes Tumor-Induced T-cell Suppression and Enhances Immunotherapy in Cancer

Rescue of Notch-1 Signaling in Antigen-Specific CD8+ T Cells Overcomes Tumor-Induced T-cell Suppression and Enhances Immunotherapy in Cancer

EGR2 is critical for peripheral naïve T-cell differentiation and the T-cell response to influenza

Regulation of innate and adaptive immunity by Notch

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