IMMUNOBIOLOGY Induction of regulatory T cell–resistant helper CD4 T cells by bacterial vector

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 spontane-ous immunity to NY-ESO-1 had specific CD4 T-cell precursors with high avidity to NY-ESO-1 under tight control by CD4CD25 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 pro-cessed 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 deple-tion of CD4CD25 Treg cells, and this prevailing effect was partially blocked by disruption of interleukin-6 or glucocorticoid-induced TNF receptor (GITR) signals. Fur-thermore, S typhimurium–induced Th1 cells had higher GITR expression than peptide-induced Th1 cells and were resistant to suppression by CD4CD25 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 CD4CD25 Treg cells