T cell growth control using hapten-specific antibody/interleukin-2 receptor chimera

Sogo, Takahiro; Kawahara, Masahiro; Ueda, Hiroshi; Otsu, Makoto; Onodera, Masafumi; Nakauchi, Hiromitsu; Nagamune, Teruyuki

doi:10.1016/j.cyto.2008.12.020

Cited by 32 publications

(26 citation statements)

References 41 publications

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“…Consequently, although IL-2 constitutes a key component of current immunotherapies, a great deal of effort is being devoted to the development of novel strategies that would boost the T-cell immune response more safely. In this regard, it has been shown that IL-2-related toxicity can be partially minimized by the use of gene-engineered T cells expressing IL-2 receptor chimeras capable of transducing signals in the absence of the cytokine (12)(13). A synthetic version of IL-2 with increased affinity for IL-2 recep-tor beta chain, named superkine or super-2, has also been proven to successfully induce the proliferation of cytotoxic T cells while eliciting a reduced expansion of T reg populations (14).…”

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confidence: 99%

Nuclear Phosphoproteomic Screen Uncovers ACLY as Mediator of IL-2-induced Proliferation of CD4+ T lymphocytes

Osinalde

Mitxelena

Sanchez-Quiles

et al. 2016

Molecular & Cellular Proteomics

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Anti-cancer immunotherapies commonly rely on the use of interleukin-2 (IL-2) to promote the expansion of T lymphocytes. IL-2-dependent proliferation is the culmination of a complex network of phosphorylation-driven signaling events that impact on gene transcription through mechanisms that are not clearly understood. To study the role of IL-2 in the regulation of nuclear protein function we have performed an unbiased mass spectrometry-based study of the nuclear phosphoproteome of resting and IL-2-treated CD4 ؉ T lymphocytes. We detected 8521distinct phosphosites including many that are not yet reported in curated phosphorylation databases. Although most phosphorylation sites remained unaffected upon IL-2 treatment, 391 sites corresponding to 288 gene products showed robust IL-2-dependent regulation. Importantly, we show that ATP-citrate lyase (ACLY) is a key phosphoprotein effector of IL-2-mediated T-cell responses. ACLY becomes phosphorylated on serine 455 in T lymphocytes upon IL-2-driven activation of AKT, and depletion or inactivation of ACLY compromises IL-2-promoted T-cell growth. Mechanistically, we demonstrate that ACLY is required for enhancing histone acetylation levels and inducing the expression of cell cycle regulating genes in response to IL-2. Thus, the metabolic enzyme ACLY emerges as a bridge between cytokine signaling and proliferation of T lymphocytes, and may be an attractive candidate target for the development of more efficient anti-cancer The underlying principle of cancer immunotherapy is to eliminate malignant cells by tuning the immune system (1-2). This revolutionary way of fighting tumors was originated three decades ago when a patient suffering from metastatic melanoma was treated with the T-cell growth promoting factor interleukin-2 (IL-2) 1 (3). The success of IL-2 administration in fighting metastatic melanoma demonstrated for the first time that solely potentiating the activation of T lymphocytes could abrogate certain human cancers (4). Current immunotherapy approaches include the use of autologous gene-engineered T cells that, once expanded ex vivo with IL-2, are re-infused back into patients by the so-called adoptive cell transfer therapy (ACT) (5-7). Despite the promising results of this approach, a safe and long-lasting expansion of transferred T cells remains a major challenge because of the undesirable side effects derived from the use of IL-2. Continued exposure to high doses of IL-2 results in increased susceptibility of T cells to apoptosis (8). Moreover, IL-2 is also a critical component for regulatory T-cell (T reg ) development and function (9 -10), and as such it functions as a negative regulator of the immune response (11). Consequently, although IL-2 constitutes a key component of current immunotherapies, a great deal of effort is being devoted to the development of novel strategies that would boost the T-cell immune response more safely. In this regard, it has been shown that IL-2-related toxicity can be partially minimized by the use of gene-engineered T cells ex...

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mentioning

confidence: 99%

Nuclear Phosphoproteomic Screen Uncovers ACLY as Mediator of IL-2-induced Proliferation of CD4+ T lymphocytes

Osinalde

Mitxelena

Sanchez-Quiles

et al. 2016

Molecular & Cellular Proteomics

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“…Consequently, the gene-transduced cells were successfully amplified by signaling through S-IR. Although we have previously constructed a series of antibody/receptor chimeras (Kaneko et al 2012;Kawahara et al 2004aKawahara et al , 2011Liu et al 2009;Sogo et al 2009;Tanaka et al 2009), this is the first report utilizing IR as a signaling domain.…”

Section: Discussionmentioning

confidence: 99%

“…However, the role of HRs is not entirely clarified due to the concurrent expression of homodimeric IR and IGF-1R. In our previous studies we succeeded the activation of chimeric receptors by using the homodimeric fluorescein tethered with a palindromic oligo-DNA linker (Kaneko et al 2012;Kawahara et al 2004a;Sogo et al 2009). If the cytoplasmic domains of IR and IGF-1R are, respectively, fused to scFvs with different specificities, the resultant chimeric receptors could exclusively form the heterodimer of scFv-IR and scFv-IGF-1R by heterodimeric antigens tethered with the oligo-DNA linker.…”

Section: Discussionmentioning

confidence: 99%

“…pBS-IR-myc was digested with EcoRV and BamHI, and ligated into EcoRV-and BamHI-digested pBS-Eb-IG (Sogo et al 2008) to create pBS-E-IR-myc-IG. pBS-E-IR-myc-IG was digested with BspEI and BamHI, and inserted into BspEI-and BamHI-digested pMK-Sb-IG (Sogo et al 2009), which is a bicistronic retroviral plasmid encoding anti-FL scFv-IL-2Rb chimera and enhanced green fluorescent protein (EGFP) genes, to make pMK-S-IR-myc-IG. This final product encodes the myc-tagged S-IR gene upstream of an internal ribosomal entry site (IRES)-EGFP cassette.…”

Section: Vector Constructionmentioning

confidence: 99%

“…For example, chimeric receptors consisting of anti-fluorescein (FL) single chain Fv (scFv), the extracellular D2 domain of erythropoietin receptor (EpoR) and the transmembrane/intracellular domains of EpoR (Liu et al 2009), gp130 (Kawahara et al 2004a), interleukin-2 receptor (IL-2R) (Sogo et al 2009) or c-Mpl (Kawahara et al 2011) transduced a growth signal in several hematopoietic cell lines and primary cells. Moreover, the chimeric receptors harboring the intracellular domain of the epidermal growth factor receptor (EGFR) (Tanaka et al 2009), c-Fms (Tanaka et al 2009) or c-Kit (Kaneko et al 2012) that belong to the RTK family as well as IR, proved to be functional in both hematopoietic and fibroblast cell lines.…”

Section: Introductionmentioning

confidence: 99%

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Construction of antibody/insulin receptor chimera for growth induction of mammalian cells

et al. 2013

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The insulin receptor (IR) is expressed ubiquitously in various tissues, where insulin exerts various biological effects on the target cells, such as cellular metabolic changes, cell proliferation and differentiation. Therefore, mimicry of insulin signaling would be a promising strategy to realize artificial control of such cellular fates. In this study, we constructed an antibody/insulin receptor chimera that enables to utilize any antigen as the ligand in principle. We constructed chimeric receptors consisting of antifluorescein single chain Fv (scFv), the extracellular D2 domain of erythropoietin receptor and the transmembrane/intracellular domains of IR (scFv-IR; S-IR). The function of S-IR was evaluated in terms of growth signal transduction in murine pro-B Ba/F3 cells and murine fibroblast NIH/3T3 cells. S-IR exerted IL-3-independent cell growth in Ba/F3 cells, while NIH/ 3T3 cells expressing S-IR acquired growth advantage over parental NIH/3T3 cells in a low-serum condition. S-IR induced phosphorylation of S-IR itself and key signaling molecules downstream of IR. Although antigen-independent activation was significantly observed, S-IR enabled specific amplification of the gene-transduced cells.

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S‐Fms signalobody enhances myeloid cell growth and migration

Kawahara

Hitomi

Nagamune

2014

Biotechnology Journal

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Since receptor tyrosine kinases (RTKs) control various cell fates in many types of cells, mimicry of RTK functions is promising for artificial control of cell fates. We have previously developed single-chain Fv (scFv)/receptor chimeras named signalobodies that can mimic receptor signaling in response to a specific antigen. While the RTK-based signalobodies enabled us to control cell growth and migration, further extension of applicability in another cell type would underlie the impact of the RTK-based signalobodies. In this study, we applied the scFv-c-Fms (S-Fms) signalobody in a murine myeloid progenitor cell line, FDC-P1. S-Fms transduced a fluorescein-conjugated BSA (BSA-FL)-dependent growth signal and activated downstream signaling molecules including MEK, ERK, Akt, and STAT3, which are major constituents of Ras/MAPK, PI3K/Akt, and JAK/STAT signaling pathways. In addition, S-Fms transduced a migration signal as demonstrated by the transwell-based migration assay. Direct real-time observation of the cells further confirmed that FDC/S-Fms cells underwent directional cell migration toward a positive gradient of BSA-FL. These results demonstrated the utility of the S-Fms signalobody for controlling growth and migration of myeloid cells. Further extension of our approach includes economical large-scale production of practically relevant blood cells as well as artificial control of cell migration for tissue regeneration and immune response.

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T cell growth control using hapten-specific antibody/interleukin-2 receptor chimera

Cited by 32 publications

References 41 publications

Nuclear Phosphoproteomic Screen Uncovers ACLY as Mediator of IL-2-induced Proliferation of CD4+ T lymphocytes

Nuclear Phosphoproteomic Screen Uncovers ACLY as Mediator of IL-2-induced Proliferation of CD4+ T lymphocytes

Construction of antibody/insulin receptor chimera for growth induction of mammalian cells

S‐Fms signalobody enhances myeloid cell growth and migration

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