Altered T-cell receptor + CD28-mediated signaling and blocked cell cycle progression in interleukin 10 and transforming growth factor-β–treated alloreactive T cells that do not induce graft-versus-host disease

Boussiotis, Vassiliki A.; Chen, Zong Ming; Zeller, Jay C.; Murphy, William J.; Berezovskaya, Alla; Narula, Satwant K.; Roncarolo, Maria Grazia; Blazar, Bruce R.

doi:10.1182/blood.v97.2.565

Cited by 45 publications

(40 citation statements)

References 70 publications

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“…TGF-b has been found to down-regulate ZAP-70 phosphorylation by activation of the protein tyrosine phosphatase SHP-1 [34,35], and therefore it is possible that hCDR1-induced up-regulation in TGF-b reinforced the action of hCDR1 and contributed to the observed down-regulation of TCR signaling. Moreover, similarly to the in vivo treatment with hCDR1, incubation of 16/6Id-immunized murine T cells with TGF-b significantly up-regulated Foxj1 and Foxo3a expression (Fig.…”

Section: Discussionmentioning

confidence: 99%

The negative regulators Foxj1 and Foxo3a are up‐regulated by a peptide that inhibits systemic lupus erythematosus‐associated T cell responses

et al. 2006

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A peptide (hCDR1) based on the complementarity determining region-1 of an anti-DNA antibody ameliorates systemic lupus erythematosus (SLE) in induced and spontaneous lupus models. Our objectives were to determine the effects of hCDR1 on TCR signaling and on its negative regulators, Foxj1 and Foxo3a. BALB/c mice were immunized with the SLE-inducing anti-DNA antibody, designated 16/6Id, and treated with hCDR1. hCDR1 treatment specifically inhibited IFN-c secretion by T cells in association with down-regulated T-bet expression and NF-jB activation; however, GATA-3 expression was not affected. Furthermore, TCR signaling (ZAP-70 phosphorylation) was inhibited, and the mRNA expression of the two modulators of Th1 activation, Foxj1 and Foxo3a, was significantly up-regulated. The latter were also elevated in SLE-afflicted (NZBÂNZW)F1 mice that were treated with hCDR1. Addition of TGF-b, which was elevated following treatment with hCDR1, to T cells from 16/6Id immunized mice, upregulated Foxj1 and Foxo3a mRNA expression, similarly to hCDR1. In contrast, anti-TGF-b antibodies added to hCDR1-treated T cells abrogated its effect. Thus, hCDR1 elevates TGF-b, which contributes to the up-regulation of T cell Foxj1 and Foxo3a expression, leading to inhibition of NF-jB activation and IFN-c secretion, which is required for the maintenance of SLE.

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Section: Discussionmentioning

confidence: 99%

The negative regulators Foxj1 and Foxo3a are up‐regulated by a peptide that inhibits systemic lupus erythematosus‐associated T cell responses

et al. 2006

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“…67 Via its effects on Cdk2, roscovitine has been shown to reduce human alloreactive responses without impairing key responses to tumor (WT-1) or viral (cytomegalovirus, Epstein-Barr virus) antigens. 68 Furthermore, defective activation of Cdk2 (along with Cdk4 and 6) has been associated with tolerance induced by IL-10 and transforming growth factor b 69 and with a reduction in experimental GVHD. 32 These data notwithstanding, the administration of roscovitine at the dose and schedule delivered did effectivity abrogate Cdk5 activity and, consistent with a previous report, 32 was associated with a reduction in clinical GVHD and preservation of GVL effects (Figure 7).…”

Section: /2cmentioning

confidence: 99%

Cyclin-dependent kinase 5 activity is required for allogeneic T-cell responses after hematopoietic cell transplantation in mice

Askew

Pareek

Eid

et al. 2017

Blood

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“…It has been previously shown that alloantigen-specific human T cells rendered anergic by lack of costimulation through CD28 are arrested at the G 1 phase of the cell cycle (24). Moreover, alloreactive mouse T cell clones that have been rendered tolerant by CD40 blockade or TGF-␤1/ IL-10 treatment and do not induce GvHD in vivo fail to progress into the late G 1 phase and to enter the S phase of the cell cycle (21,24,25,36). Our findings indicate that VIP-tolerant T cells are cell cycle arrested (Fig.…”

Section: Vip-tolerant T Cells Are Arrested In G 1 Phase and Fail To Pmentioning

confidence: 99%

Induction of Alloantigen-Specific Human T Regulatory Cells by Vasoactive Intestinal Peptide

Pozo

Anderson

González‐Rey

2009

The Journal of Immunology

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T regulatory cells (Tregs) are instrumental in the maintenance of immunological tolerance. Although Treg-based immunotherapy proved successful in preclinical autoimmunity and transplantation, factors involved in the generation of human Ag-specific Tregs are poorly known. In this study, we show that treatment of human CD4+CD25− T cells with the cytokine-like vasoactive intestinal peptide (VIP) during in vitro stimulation induces an anergic FoxP3+CD4+CD25high T cell subset displaying potent regulatory activities against allospecific effector T cells, irrespective of the presence of naturally occurring Tregs. VIP-tolerant T cells are characterized by incapability to progress to S phase of cell cycle during stimulation with HLA-disparate APCs by negatively affecting the synthesis of cyclins D3 and E, the activation of cyclin-dependent kinases (cdk)2 and cdk4, and the down-regulation of the cdk inhibitor p27kip1. VIP interaction with the type 1 VIP receptor and subsequent activation of cAMP/protein kinase A pathway play a major role in all these effects. Moreover, VIP-tolerant T cells protect against acute graft-vs-host disease in a mouse model of allogeneic bone marrow transplantation. The infusion of VIP-tolerant T cells together with the graft significantly reduces the clinical signs and mortality rate typical of the graft-vs-host disease. These effects are mediated by impairing allogeneic haplotype-specific responses of donor CD4+ cells in the transplanted animals. Our results suggest that including alloantigen-specific VIP-generated Tregs may be a valuable tool in therapeutic interventions to promote immunotolerance toward allogeneic grafts and to reduce the need of general immunosuppressive drugs.

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Altered T-cell receptor + CD28-mediated signaling and blocked cell cycle progression in interleukin 10 and transforming growth factor-β–treated alloreactive T cells that do not induce graft-versus-host disease

Cited by 45 publications

References 70 publications

The negative regulators Foxj1 and Foxo3a are up‐regulated by a peptide that inhibits systemic lupus erythematosus‐associated T cell responses

The negative regulators Foxj1 and Foxo3a are up‐regulated by a peptide that inhibits systemic lupus erythematosus‐associated T cell responses

Cyclin-dependent kinase 5 activity is required for allogeneic T-cell responses after hematopoietic cell transplantation in mice

Induction of Alloantigen-Specific Human T Regulatory Cells by Vasoactive Intestinal Peptide

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