title: The Wilms' tumor antigen is a novel target for human CD4+ regulatory T cells: implications for immunotherapy.
abstract: Compelling evidences indicate a key role for regulatory T cells (T(reg)) on the host response to cancer. The Wilms' tumor antigen (WT1) is overexpressed in several human leukemias and thus considered as promising target for development of leukemia vaccine. However, recent studies indicated that the generation of effective WT1-specific cytotoxic T cells can be largely affected by the presence of T(regs). We have generated T-cell lines and clones that specifically recognized a WT1-84 (RYFKLSHLQMHSRKH) peptide in an HLA-DRB1*0402-restricted manner. Importantly, they recognized HLA-DRB1*04-matched fresh leukemic cells expressing the WT1 antigen. These clones exerted a T helper 2 cytokine profile, had a CD4(+)CD25(+)Foxp3(+)GITR(+)CD127(-) T(reg) phenotype, and significantly inhibited the proliferative activity of allogeneic T cells independently of cell contact. Priming of alloreactive T cells in the presence of T(regs) strongly inhibited the expansion of natural killer (NK), NK T, and CD8(+) T cells and had an inhibitory effect on NK/NK T cytotoxic activity but not on CD8(+) T cells. Furthermore, priming of T cells with the WT1-126 HLA-A0201-restricted peptide in the presence of T(regs) strongly inhibited the induction of anti-WT1-126 CD8(+) CTL responses as evidenced by both very low cytotoxic activity and IFN-gamma production. Moreover, these T(reg) clones specifically produced granzyme B and selectively induced apoptosis in WT1-84-pulsed autologous antigen-presenting cells but not in apoptotic-resistant DR4-matched leukemic cells. Importantly, we have also detected anti-WT1-84 interleukin-5(+)/granzyme B(+)/Foxp3(+) CD4(+) T(regs) in five of eight HLA-DR4(+) acute myeloid leukemia patients. Collectively, our in vitro and in vivo findings strongly suggest important implications for the clinical manipulation of T(regs) in cancer patients.
authors.affiliation: Tumor Immunology Section, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Lehe
authors.forename: Hazem
authors.initials: H
authors.lastname: Ghebeh
authors.forename: Abdullah
authors.initials: A
authors.lastname: Al-Sulaiman
authors.forename: Ghofran
authors.initials: G
authors.lastname: Al Qudaihi
authors.forename: Khaled
authors.initials: K
authors.lastname: Al-Hussein
authors.forename: Fahad
authors.initials: F
authors.lastname: Almohareb
authors.forename: Naeem
authors.initials: N
authors.lastname: Chaudhri
authors.forename: Fahad
authors.initials: F
authors.lastname: Alsharif
authors.forename: Hazza
authors.initials: H
authors.lastname: Al-Zahrani
authors.forename: Abdelghani
authors.initials: A
authors.lastname: Tbakhi
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Aljurf
authors.forename: Said
authors.initials: S
authors.lastname: Dermime
mesh_terms: D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm / Q000276:immunology*; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007167:Immunotherapy; D008969:Molecular Sequence Data; D020133:Reverse Transcriptase Polymerase Chain Reaction; D009396:Wilms Tumor / Q000276:immunology* / Q000628:therapy
chemical_list: D000951:Antigens, Neoplasm; D017931:DNA Primers