Inhibition of T Cell and Promotion of Natural Killer Cell Development by the Dominant Negative Helix Loop Helix Factor Id3

Heemskerk, Mirjam H.M.; Blom, Bianca; Nolan, Garry P.; Stegmann, Alexander P.A.; Bakker, Arjen Q.; Weijer, Kees; C.M., Pieter; Spits, Hergen

doi:10.1084/jem.186.9.1597

Cited by 247 publications

(214 citation statements)

References 27 publications

(43 reference statements)

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“…Their thymus is characterized by an accumulation of CD4 -CD8 -CD44 + CD25 -thymocytes [44]. Enforced expression of Id3 in human T lineage precursor cells also suppresses thymocyte development [45]. Thus, induction of Id1 expression leading to inhibition of E-protein activity is a likely mechanism for the growth inhibitory effect of BMP-6 on Jurkat Tag cells.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory effects and target genes of bone morphogenetic protein 6 in Jurkat TAg cells

et al. 2007

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Bone morphogenetic proteins (BMP) are multifunctional cytokines that belong to the TGF-b superfamily. BMP have been shown to regulate haematopoietic stem cells, B lymphopoiesis and early thymocyte differentiation. In the present study we explored the role of BMP-6 in Jurkat TAg cells. BMP-6 rapidly induced phosphorylation of Smad1/5/8, p38 and ERK1/2, followed by a potent up-regulation of ID1, ID2 and ID3. ID1 and ID3 were also induced at the protein level. Genome-wide expression profiling of cells treated with BMP-6 compared to medium confirmed that ID1-ID3 were target genes of BMP-6 together with Noggin and Smad6. Furthermore, several genes involved in transcriptional regulation were also identified, including NFKBIA, HEY1, DLX2, KLF10 and early growth response 1. Stimulation with BMP-6 exerted an antiproliferative effect that was counteracted by inhibitor of DNA binding (Id)1 siRNA, indicating that Id1 is an important downstream mediator in Jurkat TAg cells. A subset of CD4 + T cells were found to express the BMP receptors Alk-2 and Alk-3 (type I), in addition to BMPRII (type II). BMP-6 also induced phosphorylation of Smad1/5/8, followed by transcriptional increase in ID1-ID3 mRNA expression. However, we did not observe significant changes in Id protein expression in CD4 + T cells. Altogether, the data indicate a role for BMP-6 in human T lineage cells.

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Section: Discussionmentioning

confidence: 99%

Inhibitory effects and target genes of bone morphogenetic protein 6 in Jurkat TAg cells

et al. 2007

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“…TCR-transduced CD4 + T-cell clones were detected, which produced both IFNg and IL-4 (Th0), or IFNg (Th1), or IL-4 (Th2). The TCR-transferred CD4 + T cells exerted DBY-specific cytolytic activity upto 26% in a 4-h 51 Cr-release assay, Functional transfer of HLA class II restricted TCR LT van der Veken et al and the specific lysis increased upto 100% after 19 h. Although TCR-transferred CD4 + T-cell clones were obtained that were as cytolytic as the parental JBB4 T cell clone (Figures 2b and 5), variation was observed in the levels of cytolytic activity of the TCR-transferred T-cell clones. We previously demonstrated that TCRtransferred T-cell clones can have different expression levels of the introduced TCR, explaining the observed variation in cytolytic activity.…”

Section: Discussionmentioning

confidence: 99%

“…At the highest CMA concentration (1000 nM) specific target cell lysis was completely blocked (Figure 5b). High amounts of CMA were found not to be toxic to both target cells and T cells, since no increased spontaneous 51 Cr release by the target cells was observed, and no decrease in the number of viable T cells was indicated by eosine staining.…”

Section: Mechanism Of Target Cell Lysis Of the Tcr-transduced T-cell mentioning

confidence: 93%

“…Subsequently, the identity of the PCR products was confirmed by sequencing. The TCRa and TCRb chains were cloned into bicistronic retroviral vectors containing the marker genes eGFP 51 and truncated nerve growth factor receptor (DNGF-R), 52 respectively. The Moloney murine leukemia virus-based retroviral vector LZRS and packaging cells j-NX-A were used.…”

Section: Construction Of the Retroviral Vectors And Production Of Thementioning

confidence: 99%

“…The transduction was performed using recombinant human fibronectin fragments CH-296 55 (Bio Whittaker, Verviers, Belgium) as described. 51 The transduction efficiency as measured by the expression of the markers eGFP and NGF-R was analyzed by flow cytometry 3-5 days after transduction. Subsequently, the EBV-LCL were sorted on the basis of the expression of the marker genes eGFP or DNGF-R using a FACS Vantage (Becton Dickinson (BD), San Jose, USA).…”

Section: Construction Of the Retroviral Vectors And Production Of Thementioning

confidence: 99%

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HLA class II restricted T-cell receptor gene transfer generates CD4+ T cells with helper activity as well as cytotoxic capacity

et al. 2005

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Both cytotoxic T cells and helper T cells are important in immune responses against pathogens and malignant cells.In hematological malignancies which express HLA class II molecules, immunotherapy may be directed to HLA class II restricted antigens. We investigated whether it is possible to engineer HLA class II restricted T cells with both antigenspecific cytolytic activity and the capacity to produce high amounts of cytokines. CD4 + and CD8 + peripheral-bloodderived T cells were retrovirally transduced with the HLA class II restricted minor histocompatibility antigen dead box RNA helicase Y (DBY)-specific TCR. The TCR-transduced CD4 + T cells exerted DBY-specific cytolytic activity, produced Th0, Th1, or Th2 cytokines, and proliferated upon DBY-specific stimulation. TCR-transduced CD8 + T cells exerted cytolytic activity which equaled the level of cytolytic activity of the TCR-transferred CD4 + T cells. Cotransfer of CD4 enhanced the cytolytic activity of the TCR-transduced CD8 + T cells, but introduction of CD4 was not sufficient to generate DBY-specific CD8 + T cells with the capacity to produce high amounts of cytokines. In this study, we demonstrated the feasibility to engineer T cells with antigen-specific cytolytic activity, as well as the ability to produce significant amounts of cytokines, by TCR transfer to CD4 + T cells. Gene Therapy (2005) IntroductionPatients relapsing from leukemia after allogeneic stem cell transplantation can successfully be treated by donor lymphocyte infusions (DLI), due to the graft-versusleukemia (GVL) response of the donor-derived T cells. [1][2][3][4] However, DLI is also associated with graft-versus-hostdisease (GVHD). Several studies have illustrated that depletion of CD8 + T cells from the DLI may preserve the beneficial GVL reactivity without the induction of GVHD, indicating that the CD4 + T lymphocytes may play an essential role in the antileukemic reactivity. [5][6][7][8][9][10] The mechanism by which the CD4 + T cells contribute to the GVL response is, however, not known. CD4 + T cells have been suggested to elicit the antileukemic response via the induction of minor histocompatibility antigen (mHag)-specific CD8 + T cells. 5 In addition, mHag-specific CD4 + T-helper cells have been reported to mature dendritic cells and enhance the expansion of mHag-specific cytotoxic T lymphocytes in vitro. 11 Alternatively, we have demonstrated that CD4 + T cells are capable of exerting direct cytolytic activity against leukemic cells. [12][13][14] Cellular immunotherapeutic approaches based on the adoptive transfer of T lymphocytes may require large cell numbers. Large numbers of T cells with a defined antigen specificity can be acquired by retroviral transfer of the T-cell receptor to peripheral-blood-derived T lymphocytes. Until now, the application of retroviral transfer of TCRs has mainly been limited to the transfer of HLA class I restricted TCRs. [15][16][17][18][19][20] However, the specificity of HLA class II restricted T lymphocytes can also be transferred to other T c...

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Transcriptional regulation of lymphocyte lineage commitment

1999

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The development of T cells and B cells from pluripotent hematopoietic precursors occurs through a stepwise narrowing of developmental potential that ends in lineage commitment. During this process, lineage‐specific genes are activated asynchronously, and lineage‐inappropriate genes, although initially expressed, are asynchronously turned off. These complex gene expression events are the outcome of the changes in expression of multiple transcription factors with partially overlapping roles in early lymphocyte and myeloid cell development. Key transcription factors promoting B‐cell development and candidates for this role in T‐cell development are discussed in terms of their possible modes of action in fate determination. We discuss how a robust, stable, cell‐type–specific gene expression pattern may be established in part by the interplay between endogenous transcription factors and signals transduced by cytokine receptors, and in part by the network of effects of particular transcription factors on each other. BioEssays 21:726–742, 1999. © 1999 John Wiley & Sons, Inc.

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Inhibition of T Cell and Promotion of Natural Killer Cell Development by the Dominant Negative Helix Loop Helix Factor Id3

Cited by 247 publications

References 27 publications

Inhibitory effects and target genes of bone morphogenetic protein 6 in Jurkat TAg cells

Inhibitory effects and target genes of bone morphogenetic protein 6 in Jurkat TAg cells

HLA class II restricted T-cell receptor gene transfer generates CD4+ T cells with helper activity as well as cytotoxic capacity

Transcriptional regulation of lymphocyte lineage commitment

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