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Blood, 1 February 2008, Vol. 111, No. 3, pp. 1378-1386. Prepublished online as a Blood First Edition Paper on November 16, 2007; DOI 10.1182/blood-2007-01-069450. This Article Full Text (PDF) All Versions of this Article: blood-2007-01-069450v1 111/3/1378    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kim, Y.-J. Articles by Broxmeyer, H. E. Search for Related Content PubMed PubMed Citation Articles by Kim, Y.-J. Articles by Broxmeyer, H. E. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted January 26, 2007 Accepted October 20, 2007 4-1BB regulates NKG2D costimulation in human cord blood CD8+ T cells Young-June Kim*, Myung-Kwan Han, and Hal E. Broxmeyer Department of Microbiology & Immunology, Indiana University School of Medicine, Indianapolis, IN, United States The Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN, United States The Walther Cancer Institute, Indianapolis, IN, United States * Corresponding author; email: yjkim{at}iupui.edu. Ligation of NKG2D, a potent costimulatory receptor, can be either beneficial or detrimental to CD8+ cytotoxic T cell (CTL) responses. Factors for these diverse NKG2D effects remain elusive. In this study, we demonstrate that 4-1BB, another costimulatory receptor, is an essential regulator of NKG2D in CD8+ T cells. Costimulation of NKG2D caused down-modulation of NKG2D, but induced 4-1BB expression on the cell surface, even in the presence of TGF-1 which inhibits 4-1BB expression. Resulting NKG2D-4-1BB+ cells were activated but still in an immature state with low cytotoxic activity. However, subsequent 4-1BB costimulation induced cytotoxic activity and restored down-modulated NKG2D. The cytotoxic activity and NKG2D expression induced by 4-1BB on NKG2D+4-1BB+ cells were refractory to TGF-1 down-modulation. Such 4-1BB effects were enhanced by IL-12. In contrast, in the presence of IL-4, 4-1BB effects were abolished because IL-4 down-modulated NKG2D and 4-1BB expression in cooperation with TGF-1, generating another CD8+ T cell type lacking both NKG2D and 4-1BB. These NKG2D-4-1BB- cells were inert and unable to gain cytotoxic activity. Our results suggest that 4-1BB plays a critical role in protecting NKG2D from TGF-1-mediated down-modulation. Co-expression of NKG2D and 4-1BB may represent an important biomarker for defining competency of tumor infiltrating CD8+ T cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: Y. Zhao, Q. J. Wang, S. Yang, J. N. Kochenderfer, Z. Zheng, X. Zhong, M. Sadelain, Z. Eshhar, S. A. Rosenberg, and R. A. Morgan A Herceptin-Based Chimeric Antigen Receptor with Modified Signaling Domains Leads to Enhanced Survival of Transduced T Lymphocytes and Antitumor Activity J. Immunol., November 1, 2009; 183(9): 5563 - 5574. [Abstract] [Full Text] [PDF]

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