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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-Tyr{sup 319}, LAT-Tyr{sup 191}, 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.

Authors:
 [1]; ;  [2];  [1]
  1. Department of Biotechnology, Yonsei University, Seodaemun-Gu, Shinchon-Dong 134, Seoul 120-749 (Korea, Republic of)
  2. Department of Immunobiology, Yale University School of Medicine, New Haven CT 06520 (United States)
Publication Date:
OSTI Identifier:
22199644
Resource Type:
Journal Article
Journal Name:
Biochemical and Biophysical Research Communications
Additional Journal Information:
Journal Volume: 381; Journal Issue: 3; Other Information: Copyright (c) 2009 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0006-291X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; DRUGS; GENES; INFLAMMATION; INHIBITION; MUTANTS; PHOSPHORYLATION; RECEPTORS; SECRETION; SIGNALS; STIMULATION; TRANSCRIPTION

Citation Formats

Kim, Kyun-Do, Choi, Je-Min, Chae, Wook-Jin, Lee, Sang-Kyou, and ForHumanTech Co., Ltd., Kowoon Institute of Technology Innovation, Bldg. 706, Suwon. Synergistic inhibition of T-cell activation by a cell-permeable ZAP-70 mutant and ctCTLA-4. United States: N. p., 2009. Web. doi:10.1016/J.BBRC.2009.02.046.
Kim, Kyun-Do, Choi, Je-Min, Chae, Wook-Jin, Lee, Sang-Kyou, & ForHumanTech Co., Ltd., Kowoon Institute of Technology Innovation, Bldg. 706, Suwon. Synergistic inhibition of T-cell activation by a cell-permeable ZAP-70 mutant and ctCTLA-4. United States. https://doi.org/10.1016/J.BBRC.2009.02.046
Kim, Kyun-Do, Choi, Je-Min, Chae, Wook-Jin, Lee, Sang-Kyou, and ForHumanTech Co., Ltd., Kowoon Institute of Technology Innovation, Bldg. 706, Suwon. 2009. "Synergistic inhibition of T-cell activation by a cell-permeable ZAP-70 mutant and ctCTLA-4". United States. https://doi.org/10.1016/J.BBRC.2009.02.046.
@article{osti_22199644,
title = {Synergistic inhibition of T-cell activation by a cell-permeable ZAP-70 mutant and ctCTLA-4},
author = {Kim, Kyun-Do and Choi, Je-Min and Chae, Wook-Jin and Lee, Sang-Kyou and ForHumanTech Co., Ltd., Kowoon Institute of Technology Innovation, Bldg. 706, Suwon},
abstractNote = {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-Tyr{sup 319}, LAT-Tyr{sup 191}, 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.},
doi = {10.1016/J.BBRC.2009.02.046},
url = {https://www.osti.gov/biblio/22199644}, journal = {Biochemical and Biophysical Research Communications},
issn = {0006-291X},
number = 3,
volume = 381,
place = {United States},
year = {Fri Apr 10 00:00:00 EDT 2009},
month = {Fri Apr 10 00:00:00 EDT 2009}
}