title: Induction of regulatory T cell-resistant helper CD4+ T cells by bacterial vector.
abstract: 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.
authors.affiliation: Ludwig Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Nishikawa
authors.forename: Takemasa
authors.initials: T
authors.lastname: Tsuji
authors.forename: Elke
authors.initials: E
authors.lastname: Jäger
authors.forename: Gabriel
authors.initials: G
authors.lastname: Briones
authors.forename: Gerd
authors.initials: G
authors.lastname: Ritter
authors.forename: Lloyd J
authors.initials: LJ
authors.lastname: Old
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Galán
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shiku
authors.forename: Sacha
authors.initials: S
authors.lastname: Gnjatic
mesh_terms: D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D005822:Genetic Vectors / Q000235:genetics*; D053450:Glucocorticoid-Induced TNFR-Related Protein; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D015850:Interleukin-6 / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000276:immunology; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000276:immunology; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology; D012486:Salmonella typhimurium / Q000235:genetics* / Q000276:immunology*; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*
chemical_list: D000951:Antigens, Neoplasm; C104948:CTAG1B protein, human; D053450:Glucocorticoid-Induced TNFR-Related Protein; D053645:Interleukin-2 Receptor alpha Subunit; D015850:Interleukin-6; D008565:Membrane Proteins; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C491405:TNFRSF18 protein, human