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Blood, 1 January 2005, Vol. 105, No. 1, pp. 274-281. Prepublished online as a Blood First Edition Paper on September 7, 2004; DOI 10.1182/blood-2003-12-4343. This Article Full Text (PDF) All Versions of this Article: 2003-12-4343v1 105/1/274    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 December 22, 2003 Accepted August 18, 2004 Modulation of Cord Blood CD8+ T cell Effector Differentiation by TGF-1 and 4-1BB Costimulation Young-June Kim, Teresa M Stringfield, Yan Chen, and Hal E Broxmeyer* Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA; Walther Cancer Institute, Indiana University School of Medicine, Indianapolis, IN, USA Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA; Walther Cancer Institute, Indiana University School of Medicine, Indianapolis, IN, USA * Corresponding author; email: hbroxmey{at}iupui.edu. Transforming growth factor-1 (TGF-1), an immunosuppressive cytokine, inhibits CTL immune responses. In contrast, 4-1BB (CD137), a costimulatory molecule in the TNF receptor family, amplifies CTL-mediated anti-tumor immune responses. We investigated whether TGF-1 responses could be reversed by 4-1BB costimulation during in vitro differentiation of naive CD8+ T cells into effector CTL cells. TGF-1 potently suppressed CTL differentiation of human cord blood naive CD8+ T cells as determined by reduced induction of characteristic phenotypes of effector cells and cytotoxic activity. TGF-1-mediated suppression of CTL differentiation was abrogated by 4-1BB costimulation, but not by CD28 or another member in the TNF receptor family, CD30. 4-1BB costimulation suppressed Smad2 phosphorylation induced by TGF-1, suggesting that 4-1BB effects were at the level of TGF-1 signaling. 4-1BB effects on the TGF-1-mediated suppression were enhanced by IL-12, but counteracted by IL-4; 4-1BB expression was up- or down-regulated respectively by IL-12 and IL-4. IL-4 was more dominant than IL-12 when both cytokines were present during 4-1BB costimulation in the presence of TGF-1. This indicates critical roles for IL-4 and IL-12 in regulating 4-1BB effects on TGF-1-mediated suppression. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: Y.-J. Kim, M.-K. Han, and H. E. Broxmeyer 4-1BB regulates NKG2D costimulation in human cord blood CD8+ T cells Blood, February 1, 2008; 111(3): 1378 - 1386. [Abstract] [Full Text] [PDF] K. G. Elpek, E. S. Yolcu, D. D. H. Franke, C. Lacelle, R.-H. Schabowsky, and H. Shirwan Ex Vivo Expansion of CD4+CD25+FoxP3+ T Regulatory Cells Based on Synergy between IL-2 and 4-1BB Signaling J. Immunol., December 1, 2007; 179(11): 7295 - 7304. [Abstract] [Full Text] [PDF] K.-D. Park, L. Marti, J. Kurtzberg, and P. Szabolcs In vitro priming and expansion of cytomegalovirus-specific Th1 and Tc1 T cells from naive cord blood lymphocytes Blood, September 1, 2006; 108(5): 1770 - 1773. [Abstract] [Full Text] [PDF]

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