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.
Highlights
The Wilms’ tumor (WT1) gene exerts an oncogenic function in various types of leukemias [1]
During the course of our study, Fujiki and colleagues [35] described an anti-WT1 T helper 1 (Th1) T-cell clone restricted to HLA-DRB1*0405 and specific to a 16-mer WT1332-347 peptide that has an additional amino acid compared with the 15-mer WT1333-347 epitope described in our study
The antigen dose can influence the differentiation of Th1 and T helper 2 (Th2) cells [36]
Summary
The Wilms’ tumor (WT1) gene exerts an oncogenic function in various types of leukemias [1]. It has been shown recently that Tregs directly suppress the antitumor immune responses in cancer patients [5, 6], and depletion of this T-cell population resulted in an enhancement of vaccine-mediated antitumor immunity in cancer patients [7]. This highlights the role of Tregs in modulating both natural and adoptive immune responses in cancer patients. A recent study has shown the existence of tumor-specific Tregs, which actively suppress antigenspecific antitumor immunity in cancer patients [12]. Another study by Nadal and colleagues [15] suggested that Tregs exert an inhibitory effect on graft versus leukemia and this was associated with relapse after allogeneic stem cell transplantation
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