Synergistic inhibition of T-cell activation by a cell-permeable ZAP-70 mutant and ctCTLA-4

Kyun Do Kim, Je Min Choi, Wook Jin Chae, Sang Kyou Lee

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

T-cell activation requires TcR-mediated and co-stimulatory signals. ZAP-70 participates in the initial step of TcR signal transduction, while a co-receptor, CTLA-4, inhibits T-cell activation. In previous studies, the overexpression of a ZAP-70 mutant (ZAP-70-Y319F) inhibited the TcR-induced activation of NFAT and IL-2 production, while Hph-1-ctCTLA-4 prevented allergic inflammation. To develop an effective immunosuppressive protein drug that blocks both TcR-mediated and co-stimulatory signaling pathways, a fusion protein of ZAP-70-Y319F and the Hph-1 protein transduction domain was generated. Hph-1-ZAP-70-Y319F inhibited the phosphorylation of ZAP-70-Tyr319, LAT-Tyr191, and p44/42 MAPK induced by TcR stimulation, NFAT- and AP-1-mediated gene transcription, and the induction of CD69 expression and IL-2 secretion. Hph-1-ZAP-70-Y319F and Hph-1-ctCTLA-4 synergistically inhibited signaling events during T-cell activation. This is the first report to demonstrate the synergistic inhibition of signals transmitted via TcR and its co-stimulatory receptor by cell-permeable forms of intracellular signal mediators.

Original languageEnglish
Pages (from-to)355-360
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume381
Issue number3
DOIs
Publication statusPublished - 2009 Apr 10

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T-cells
Chemical activation
T-Lymphocytes
Interleukin-2
ZAP-70 Protein-Tyrosine Kinase
Mitogen-Activated Protein Kinase 3
Transcription Factor AP-1
Immunosuppressive Agents
Signal transduction
Phosphorylation
Signal Transduction
Transcription
Inflammation
Proteins
Fusion reactions
Genes
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

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title = "Synergistic inhibition of T-cell activation by a cell-permeable ZAP-70 mutant and ctCTLA-4",
abstract = "T-cell activation requires TcR-mediated and co-stimulatory signals. ZAP-70 participates in the initial step of TcR signal transduction, while a co-receptor, CTLA-4, inhibits T-cell activation. In previous studies, the overexpression of a ZAP-70 mutant (ZAP-70-Y319F) inhibited the TcR-induced activation of NFAT and IL-2 production, while Hph-1-ctCTLA-4 prevented allergic inflammation. To develop an effective immunosuppressive protein drug that blocks both TcR-mediated and co-stimulatory signaling pathways, a fusion protein of ZAP-70-Y319F and the Hph-1 protein transduction domain was generated. Hph-1-ZAP-70-Y319F inhibited the phosphorylation of ZAP-70-Tyr319, LAT-Tyr191, and p44/42 MAPK induced by TcR stimulation, NFAT- and AP-1-mediated gene transcription, and the induction of CD69 expression and IL-2 secretion. Hph-1-ZAP-70-Y319F and Hph-1-ctCTLA-4 synergistically inhibited signaling events during T-cell activation. This is the first report to demonstrate the synergistic inhibition of signals transmitted via TcR and its co-stimulatory receptor by cell-permeable forms of intracellular signal mediators.",
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Synergistic inhibition of T-cell activation by a cell-permeable ZAP-70 mutant and ctCTLA-4. / Kim, Kyun Do; Choi, Je Min; Chae, Wook Jin; Lee, Sang Kyou.

In: Biochemical and Biophysical Research Communications, Vol. 381, No. 3, 10.04.2009, p. 355-360.

Research output: Contribution to journalArticle

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