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: Hiroyoshi Nishikawa, Takemasa Tsuji, Elke Jäger, Gabriel Briones, Gerd Ritter, Lloyd J Old, Jorge E Galán, Hiroshi Shiku, Sacha Gnjatic
• Journal: Blood (Blood) Vol. 111 Issue 3 Pg. 1404-12 (Feb 01 2008) ISSN: 0006-4971 [Print] United States
• PMID: 17986662 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Neoplasm
• CTAG1B protein, human
• Glucocorticoid-Induced TNFR-Related Protein
• Interleukin-2 Receptor alpha Subunit
• Interleukin-6
• Membrane Proteins
• Receptors, Nerve Growth Factor
• Receptors, Tumor Necrosis Factor
• TNFRSF18 protein, human

Topics

• Antigens, Neoplasm (immunology, metabolism)
• Cell Differentiation (immunology)
• Cells, Cultured
• Genetic Vectors (genetics)
• Glucocorticoid-Induced TNFR-Related Protein
• Humans
• Interleukin-2 Receptor alpha Subunit (immunology)
• Interleukin-6 (pharmacology)
• Lymphocyte Activation (immunology)
• Membrane Proteins (immunology, metabolism)
• Receptors, Nerve Growth Factor (immunology)
• Receptors, Tumor Necrosis Factor (immunology)
• Salmonella typhimurium (genetics, immunology)
• Sensitivity and Specificity
• Signal Transduction (immunology)
• T-Lymphocytes, Helper-Inducer (drug effects, immunology, metabolism)