Overexpression of the Notch ligand, Jagged-1, induces alloantigen-specific human regulatory T cells

Yvon, Eric; Vigouroux, Stéphane; Rousseau, Raphaël F.; Biagi, Ettore; Amrolia, Persis; Dotti, Gianpietro; Wagner, H; Brenner, Malcolm K.

doi:10.1182/blood-2002-12-3826

Cited by 137 publications

(115 citation statements)

References 39 publications

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“…32 In the current study, we quantified the mRNA expression of Notch1, Hes1, and Hey1 in DAPTcultured PBMCs. 34,35 It was shown that Treg-triggered Notch1 activation of the target cells by membrane-bound TGF-b and blockage of Notch1 signaling reversed the immune suppression function of Treg cells. 36 Further research also revealed that Treg cells preferentially expressed cell membrane Notch ligands and that blocking Notch signaling initiated by such ligands inhibited Treg cell suppressor function.…”

Section: Discussionmentioning

confidence: 99%

Inactivation of Notch signaling reverses the Th17/Treg imbalance in cells from patients with immune thrombocytopenia

Liu

et al. 2015

Laboratory Investigation

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T helper 17 (Th17) cells and regulatory T (Treg) cells, along with Th1 and Th2 cells, may contribute to the development of immune thrombocytopenia (ITP). The imbalance of Th17/Treg toward Th17 cells has been shown to play a pivotal role in the peripheral immune response. Notch signaling has been implicated in peripheral T-cell activation and effector cell differentiation. However, the role of Th17/Treg in the pathogenesis of ITP and the effect of Notch signaling on Th17/Treg imbalances remain largely elusive in ITP. In vitro, we treated peripheral blood mononuclear cells (PBMCs) from ITP and healthy controls with g-secretase inhibitor (DAPT). Th17 cells and Treg cells were measured by flow cytometry and IL-17, IL-21, and IL-10 secretion by enzyme immunoassay technique. The mRNA expression of Ntoch1, Hes1, Hey1, RORgt, and Foxp3 was investigated by RT-PCR. Cell proliferation and apoptosis were determined by the Cell Counting Kit-8 and apoptosis detection kit. We demonstrated that DAPT was effective in inhibiting mRNA expression of Notch signaling molecules. In untreated cultured PBMCs from ITP patients, we observed elevated Th17 cell and IL-21 levels and RORgt mRNA expression, decreased Treg cells and Foxp3 mRNA expression, and an increased ratio of Th17/Treg and RORgt/Foxp3. After inactivating Notch signal by DAPT, Th17 cells and Th17/Treg ratio were dose dependently decreased and accompanied by the reduction of IL-17 in culture supernatants and RORgt mRNA expression in ITP patients. However, no significant difference was found for Treg cells and Foxp3 mRNA expression, RORgt/Foxp3 ratio, and IL-21 and IL-10 levels after DAPT treatment in ITP patients. We also present evidence that the effect of DAPT inhibition on the Th17 cell response was associated with downregulation of RORgt and IL-17 transcription using human in vitro polarization. In conclusion, our findings highlight the importance of Notch signaling in Th17/Treg imbalances in ITP. Inactivation of Notch signaling might be a potential immunoregulatory strategy in ITP patients.

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Section: Discussionmentioning

confidence: 99%

Inactivation of Notch signaling reverses the Th17/Treg imbalance in cells from patients with immune thrombocytopenia

Liu

et al. 2015

Laboratory Investigation

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“…The cells were incubated at a 1:1 ratio in 96-well plates (1 Â 10 5 cells per well for each population) with 40 Gyirradiated stimulator cells. Proliferation was measured on day 5 by [ 3 H]thymidine incorporation (22). Statistical analysis.…”

Section: Methodsmentioning

confidence: 99%

Responses to Human CD40 Ligand/Human Interleukin-2 Autologous Cell Vaccine in Patients with B-Cell Chronic Lymphocytic Leukemia

Biagi

Rousseau

Yvon

et al. 2005

Clinical Cancer Research

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Purpose: Human CD40 ligand activates the malignant B-cell chronic lymphocytic leukemia cells and enhances their capacity to present tumor antigens. Human interleukin-2 further potentiates the immunogenicity of human CD40 ligand in preclinical murine models. Experimental Design: We prepared autologous B-cell chronic lymphocytic leukemia cells that expressed both human CD40 ligand (>90% positive) and human interleukin-2 (median secretion, 1,822 pg/mL/10 6 cells; range, 174-3,604 pg). Nine patients were enrolled in a phase I trial, receiving three to eight s.c. vaccinations. Results: Vaccinations were administered without evidence of significant local or systemic toxicity. A B-cell chronic lymphocytic leukemia^specific T-cell response was detected in seven patients. The mean frequencies of IFN-g, granzyme-B, and IL-5 spot-forming cells were 1/1,230, 1/1,450, and 1/4,500, respectively, representing a 43-to 164-fold increase over the frequency before vaccine administration. Three patients produced leukemia-specific immunoglobulins.Three patients had >50% reduction in the size of affected lymph nodes. Nonetheless, the antitumor immune responses were observed only transiently once immunization ceased. High levels of circulating CD4 + /CD25 + /LAG-3 + /FoxP-3 + immunoregulatory T cells were present before, during and after treatment and in vitro removal of these cells increased the antileukemic T-cell reactivity. Conclusions:These results suggest that immune responses to B-cell chronic lymphocytic leukemia can be obtained with human CD40 ligand/human interleukin-2^expressing s.c. vaccines but that these responses are transient. High levels of circulating regulatory T cells are present, and it will be of interest to see if their removal in vivo augments and prolongs the antitumor immune response.The malignant B-cell chronic lympocytic leukemia (B-CLL) cells express a range of tumor-associated and tumor-specific antigens, including immunoglobulins. These cells also express high levels of MHC class I and II molecules but lack costimulatory molecules and are ineffective antigen-presenting cells. Their immunogenicity can be increased by manipulation of the CD40/ CD40 ligand (CD40L) pathway, in which CD40L interacts with CD40 on B-CLL target cells to increase their antigen-presenting capacity through up-regulation of the costimulatory molecules CD80 and CD86 and adhesion molecules, such as CD54 (1 -5). CD40L also induces dendritic cell maturation in vivo, increasing their ability to take up and process antigens (6 -9). These effects have encouraged studies of CD40L as immunotherapy for human B-cell malignancies, with tumor responses and disease stabilization noted in both preclinical and clinical settings (1 -5, 10 -16). Using in vitro and in vivo models, we have shown that the immunostimulatory effect obtained with human CD40L

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“…Recently, Notch has been described to be involved in these late antigen-dependent differentiation steps. Initial studies had reported the development of regulatory T cells in the mouse and human system by Jagged1-overexpressing APC [12][13][14] and the induction of IFN-c-secreting Th1 cells as the result of a Dll1/ Notch3 interaction [15]. Recently, Amsen et al [16] showed that APC generally use the Notch pathway to instruct Th cell differentiation.…”

Section: Introductionmentioning

confidence: 99%

Notch ligands Delta-like1, Delta-like4 and Jagged1 differentially regulate activation of peripheral T helper cells

et al. 2005

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Overexpression of the Notch ligand, Jagged-1, induces alloantigen-specific human regulatory T cells

Abstract: Graft-versus-host disease (GVHD

Cited by 137 publications

References 39 publications

Inactivation of Notch signaling reverses the Th17/Treg imbalance in cells from patients with immune thrombocytopenia

Inactivation of Notch signaling reverses the Th17/Treg imbalance in cells from patients with immune thrombocytopenia

Responses to Human CD40 Ligand/Human Interleukin-2 Autologous Cell Vaccine in Patients with B-Cell Chronic Lymphocytic Leukemia

Notch ligands Delta-like1, Delta-like4 and Jagged1 differentially regulate activation of peripheral T helper cells

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