Improved version of a human CD2 minigene based vector for T cell-specific expression in transgenic mice

Zhumabekov, Talgat; Corbella, Paola; Tolaini, Mauro; Kioussis, Dimitris

doi:10.1016/0022-1759(95)00124-s

Cited by 255 publications

(278 citation statements)

References 16 publications

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“…Hence, this line was used in the following studies. The VA vector has previously been shown to drive high levels of transgene expression in T cells and occasionally in B cells, but not in other cells (granulocytes, monocytes, and erythrocytes) [15,16]. We also analyzed expression of the transgene in T cells, B cells, and monocytes (Supporting Information Fig.…”

Section: Generation Of Tg Mouse Lines Overexpressing Rorγtmentioning

confidence: 99%

Overexpression of RORγt under control of the CD2 promoter induces polyclonal plasmacytosis and autoantibody production in transgenic mice

et al. 2012

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Retinoic acid related orphan receptor gamma-t (RORγt) is known to be a master regulator of Th17-cell development. In this study, we generated RORγt-overexpressing transgenic (RORγt Tg) mice in which transgene expression was driven by the CD2 promoter, and found that these mice developed polyclonal plasmacytosis and autoantibody production. RORγt Tg mice were generated on a C57BL/6 background, and also were intercrossed with BALB/c mice. BALB/c F1 (BALB/F1) RORγt Tg mice developed massive polyclonal plasmacytosis, and had shorter life spans. Splenomegaly and infiltration of plasma cells into the lung were observed. Hyperglobulinemia, anti-double-stranded DNA antibodies, antierythrocyte antibodies, and anti-platelet antibodies were detected in BALB/F1 RORγt Tg mice. In the present study, polyclonal plasmacytosis in BALB/F1 RORγt Tg mice appeared to be due to the induction of excessive IL-6 production by IL-17. We detected increased numbers of CD11b + cells that produced IL-6. We also generated IL-6-deficient RORγt Tg BALB/F1 background mice, which displayed high levels of serum IL-17, but did not develop severe hyperglobulinemia. Excessive IL-6 production by several cell types, including macrophages, in BALB/F1 RORγt Tg mice, might effect the development of plasmacytosis. These results suggest that RORγt plays important roles in the development of plasmacytosis and autoantibody production. Eur. J. Immunol. 2012Immunol. . 42: 1999Immunol. -2009 Introduction CD4 + T helper (Th) cells are a subcategory of T lymphocytes that play a central role in modulating immune responses. Classically, naïve CD4 + T cells have been thought to differentiate into two cell types, Th1 and Th2 cells. This corresponds to the Th1/Th2 paradigm proposed by Mosmann et al. [1]. More recently, a third subset of Th cells, Th17 cells, has been described; this is a distinct lineage that does not share developmental pathways with either Th1 or Th2 cells [2,3]. Th17 cells are generally thought to be proinflammatory, especially through the production of 3]. Th17 cells have been shown to participate in the development of autoimmunity, and also to play an important role in host defense against infection [4]. Expression of the transcription factor retinoic acid related orphan receptor gamma-t (RORγt) is required for the differentiation of Th17 cells [5,6]. The orphan receptor RORγt is a thymusspecific isoform of RORγ [7]. A related nuclear receptor, RORα, was shown to act in synergy with RORγt to promote the differentiation of Th17 cells [8]. STAT3 is also required for full generation of the Th17 lineage [9]. The upregulation of RORγt depends on STAT3 [9], and the selective deletion of STAT3 in T cells partially abrogates the development of Th17 cells because it also abrogates the expression of RORα and RORγt [8].IL-6 is an important cytokine in the differentiation of Th17 cells. IL-6, together with TGF-β, is required to induce IL-17 expression in naïve CD4 + T cells, which are characterized by the expression of RORγt [5,10,11]. Since its discovery i...

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Section: Generation Of Tg Mouse Lines Overexpressing Rorγtmentioning

confidence: 99%

Overexpression of RORγt under control of the CD2 promoter induces polyclonal plasmacytosis and autoantibody production in transgenic mice

et al. 2012

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“…To elucidate the mechanism of CTLA-4-mediated inhibition in vivo, we established two of each of the Tg mouse lines expressing either a full-length CTLA-4 (FL-Tg) or a mutant CTLA-4 with a truncated cytoplasmic tail lacking the tyrosine motif (TR-Tg) [24], under the control of the human CD2 promoter [29]. One of each of the lines of FL-Tg and TR-Tg mice was selected for further analysis of the in vivo function of CTLA-4.…”

Section: Establishment Of Ctla-4-tg Micementioning

confidence: 99%

“…Full-length and truncated CTLA-4 cDNA, previously described (only six amino acids remain in the truncated form) [24], were subcloned into an expression vector containing the human CD2 promoter [29]. The insert was injected into oocytes from C57BL/6 mice.…”

Section: Generation Of Ctla-4 Transgenic Micementioning

confidence: 99%

In vivo overexpression of CTLA‐4 suppresses lymphoproliferative diseases and thymic negative selection

et al. 2005

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Cytotoxic T lymphocyte antigen‐4 (CTLA‐4) induces major inhibitory signals for T cell activation. From analyses of TCR‐transgenic (Tg) CTLA‐4‐deficient mice, it has been believed that CTLA‐4 does not affect thymocyte development. To focus upon the in vivo function of CTLA‐4 in thymocyte development from a different aspect, we have established Tg mice expressing either full‐length CTLA‐4 (FL‐Tg) or a mutant CTLA‐4 lacking the cytoplasmic region (truncated, TR‐Tg), and analyzed thymocyte development. TR‐T cells express much higher CTLA‐4 on the cell surface than FL‐T cells, in which most CTLA‐4 was localized in intracellular vesicles. While CTLA‐4–/– mice exhibit lymphoproliferative disease, neither of the Tg mice with CTLA‐4–/– background developed the disorder. Although the development of thymocytes appeared normal in both Tg mice, in vivo depletion of double‐positive thymocytes by injection of anti‐CD3 Ab as well as the elimination of minor lymphocyte‐stimulating antigen‐reactive thymocytes were impaired in FL‐Tg mice but not in TR‐Tg mice. Functionally, cross‐linking of CTLA‐4 on thymocytes from FL‐Tg mice, but not from TR‐Tg mice, inhibited proliferation. These results reveal a potential role of CTLA‐4, through its cytoplasmic domain, in the negative selection of thymocytes and in the prevention of lymphoproliferative disease.

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“…49 Thus, the use of strong LCRs for high level tissue specific transcription holds great promise for sustained expression of transgenes. Since CD4 T cells are the predominant target of HIV infection we used the hCD2 gene promoter, 3′ untranslated region (UTR) and LCR as our first generation expression vector: pVA-CD2 described by Zhumabekov et al 50 In a strategy to obtain inducible higher level expression of HIV inhibitory molecules, an HIV-Tat inducible vector was constructed by substitution of the hCD2 promoter by the HIV-2 LTR to yield pVA-HIV. To increase steady state levels of RNA further, a derivative of pVA-HIV was used which contains the human ␤-globin second intron (betaIVS-II) and polyadenylation sequences in place of the endogenous CD2 3′ UTR to provide RNA stabilization.…”

Section: Resultsmentioning

confidence: 99%

High level inhibition of HIV replication with combination RNA decoys expressed from an HIV-Tat inducible vector

Fraisier

Irvine²,

Wrighton³

et al. 1998

Gene Ther

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Improved version of a human CD2 minigene based vector for T cell-specific expression in transgenic mice

Cited by 255 publications

References 16 publications

Overexpression of RORγt under control of the CD2 promoter induces polyclonal plasmacytosis and autoantibody production in transgenic mice

Overexpression of RORγt under control of the CD2 promoter induces polyclonal plasmacytosis and autoantibody production in transgenic mice

In vivo overexpression of CTLA‐4 suppresses lymphoproliferative diseases and thymic negative selection

High level inhibition of HIV replication with combination RNA decoys expressed from an HIV-Tat inducible vector

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