Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-β signals in vivoi
Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-β signals in vivoi
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DOI：
10.1073/pnas.0408197102
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发表时间：
2005-01-11
影响因子：
11.1
通讯作者：
Khazaie, K
中科院分区：
文献类型：
--
作者：
Chen, ML;Pittet, MJ;Khazaie, K
癌症患者可以携带大量对肿瘤抗原（Ag）具有特异性的CD 8和CD 4 T细胞。然而，在大多数情况下，这样的T细胞不能在体内根除肿瘤。在此，我们通过监测引流和非引流淋巴结中Ag特异性CD 4（+）CD 25（+）调节性T细胞（Treg）的归巢、扩增和效应功能，研究了体内Ag特异性CD 4（+）CD 25（+）调节性T细胞（Treg）对肿瘤特异性CD 8 T细胞免疫应答的干扰。结果显示，在存在或不存在Ag特异性Treg的情况下，CD 8细胞扩增至相同程度并产生相似水平的IFN-γ。然而，这些Treg通过特异性抑制扩增的CD 8细胞的细胞毒性来消除CD 8 T细胞介导的肿瘤排斥。抑制的分子机制涉及TGF-β，因为肿瘤特异性CD 8细胞表达显性阴性TGF-β受体使其对抑制具有抗性，并与肿瘤排斥和未受损的细胞毒性相关。
Cancer patients can harbor significant numbers of CD8 and CD4 T cells with specificities to tumor antigens (Ags). Yet, in most cases, such T cells fail to eradicate the tumor in vivo. Here, we investigated the interference of Ag-specific CD4(+)CD25(+) regulatory T cells (Treg) with the tumor-specific CD8 T cell immune response in vivo, by monitoring the homing, expansion, and effector function of both subsets in draining and nondraining lymph nodes. The results show that CD8 cells expand to the same extent and produce similar levels of IFN-gamma in the presence or absence of Ag-specific Treg. Nevertheless, these Treg abrogate CD8 T cell-mediated tumor rejection by specifically suppressing the cytotoxicity of expanded CD8 cells. The molecular mechanism of suppression involves TGF-beta because expression of a dominant-negative TGF-beta receptor by tumor-specific CD8 cells renders them resistant to suppression and is associated with tumor rejection and unimpaired cytotoxicity.