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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.
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Submitted September 19, 2007
Accepted October 28, 2007
Induction of regulatory T cell-resistant helper CD4+ T cells by bacterial vector
Hiroyoshi Nishikawa, Takemasa Tsuji, Elke Jager, Gabriel Briones, Gerd Ritter, Lloyd J Old, Jorge E Galan, Hiroshi Shiku, and Sacha Gnjatic*
Ludwig Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, NY, United States
Medizinische Klinik II, Hamatologie-Onkologie, Krankenhaus Nordwest, Frankfurt, Germany
Section of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT, United States
Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Tsu, Mie, Japan
* Corresponding author; email: gnjatics{at}mskcc.org.
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 cancer patients 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 cells (Tregs). We now found that in healthy donors and melanoma patients 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+ Tregs 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+ Tregs 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+ Tregs.
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