The Wilms' tumor antigen is a novel target for human CD4+ regulatory T cells:: Implications for immunotherapy
The Wilms' tumor antigen is a novel target for human CD4+ regulatory T cells:: Implications for immunotherapy
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DOI：
10.1158/0008-5472.can-08-0050
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发表时间：
2008-08-01
期刊：
影响因子：
11.2
通讯作者：
Dermime, Said
中科院分区：
文献类型：
--
作者：
Lehe, Cynthia;Ghebeh, Hazem;Dermime, Said
令人信服的证据表明，调节性T细胞（T(reg)）在宿主对癌症的反应中起着关键作用。Wilms肿瘤抗原（WT1）在几种人类白血病中过表达，因此被认为是开发白血病疫苗的有希望的靶点。然而，最近的研究表明，有效的wt1特异性细胞毒性T细胞的产生在很大程度上受到T（regs）存在的影响。我们以HLA-DRBI*0402限制的方式产生了特异性识别WT1-84 （RYFKLSHLQMHSRKH）肽的t细胞系和克隆。重要的是，他们识别出HLA-DRBI*04匹配的表达WT1抗原的新鲜白血病细胞。这些克隆具有T辅助2细胞因子谱，具有CD4(+)CD25(+)Foxp3(+)GITR(+)CD127(-) T（reg）表型，并且显著抑制异体T细胞的增殖活性，而不依赖于细胞接触。在T（regs）存在的情况下，启动同种异体反应性T细胞强烈抑制自然杀伤（NK）、NK T和CD8(+) T细胞的扩张，并对NK/NK T细胞毒性活性有抑制作用，但对CD8(+) T细胞没有抑制作用。此外，在T（regs）存在的情况下，用WT1-126 hla - a020i限制性肽引发T细胞强烈抑制抗WT1-126 CD8(+) CTL反应的诱导，这证明了非常低的细胞毒活性和ifn - γ的产生。此外，这些T（reg）克隆在wti -84脉冲的自体抗原呈递细胞中特异性产生颗粒酶B并选择性诱导细胞凋亡，而在抗凋亡的dr4匹配的白血病细胞中则没有。重要的是，我们还在8例HLA-DR4（+）急性髓性白血病患者中的5例中检测到抗wt1 -84白介素-5(+)/颗粒酶B(+)/Foxp3(+) CD4(+) T（regs）。总的来说，我们的体外和体内研究结果强烈建议对癌症患者T（regs）的临床操作具有重要意义。
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-DRBI*0402-restricted manner. Importantly, they recognized HLA-DRBI*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-A020I-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 WTI-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.