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Blood, 1 February 2008, Vol. 111, No. 3, pp. 1404-1412. Prepublished online as a Blood First Edition Paper on November 6, 2007; DOI 10.1182/blood-2007-09-113761. This Article Full Text Full Text (PDF) Supplemental Figure All Versions of this Article: blood-2007-09-113761v1 111/3/1404    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 CrossRef Google Scholar Articles by Nishikawa, H. Articles by Gnjatic, S. PubMed PubMed Citation Articles by Nishikawa, H. Articles by Gnjatic, S. Related Collections Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Induction of regulatory T cell–resistant helper CD4+ T cells by bacterial vector Hiroyoshi Nishikawa1,2, Takemasa Tsuji1, Elke Jäger3, Gabriel Briones4, Gerd Ritter1, Lloyd J. Old1, Jorge E. Galán4, Hiroshi Shiku2,5, and Sacha Gnjatic1 1 Ludwig Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, NY; 2 Department of Cancer Vaccine, Mie University Graduate School of Medicine, Mie, Japan; 3 Medizinische Klinik II, Hämatologie-Onkologie, Krankenhaus Nordwest, Frankfurt, Germany; 4 Section of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT; and 5 Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Mie, Japan Salmonella typhimurium engineered to deliver cancer/testis antigen NY-ESO-1 through type III secretion (S typhimurium–NY-ESO-1) was shown to be an efficient cancer vaccine construct in mice and to stimulate NY-ESO-1–specific CD8+/CD4+ T cells in vitro in patients with cancer with NY-ESO-1 spontaneous immunity. We also showed that individuals without spontaneous immunity to NY-ESO-1 had specific CD4+ T-cell precursors with high avidity to NY-ESO-1 under tight control by CD4+CD25+ regulatory T (Treg) cells. We now found that in healthy donors and patients with melanoma without NY-ESO-1 spontaneous immunity, S typhimurium–NY-ESO-1 elicits CD4+ T helper 1 (Th1) cells in vitro recognizing naturally processed antigen from these high-avidity NY-ESO-1–specific naive precursors. In contrast to peptide stimulation, induction of specific Th1 cells with S typhimurium–NY-ESO-1 did not require in vitro depletion of CD4+CD25+ Treg cells, and this prevailing effect was partially blocked by disruption of interleukin-6 or glucocorticoid-induced TNF receptor (GITR) signals. Furthermore, S typhimurium–induced Th1 cells had higher GITR expression than peptide-induced Th1 cells and were resistant to suppression by CD4+CD25+ Treg cells in a GITR-dependent fashion. We propose that S typhimurium–NY-ESO-1 induces antigen-specific T-cell responses that are resistant to suppression by CD4+CD25+ Treg cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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