Peripheral T-cell tolerance associated with prostate cancer is independent from CD4+CD25+ regulatory T cells
Peripheral T-cell tolerance associated with prostate cancer is independent from CD4+CD25+ regulatory T cells
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DOI：
10.1158/0008-5472.can-07-2429
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发表时间：
2008-01-01
期刊：
影响因子：
11.2
通讯作者：
Bellone, Matteo
中科院分区：
文献类型：
--
作者：
Degl'Innocenti, Elena;Grioni, Matteo;Bellone, Matteo
CD 4（+）CD 25（+）Foxp 3（+）调节性T细胞（Treg）被认为抑制针对肿瘤相关抗原（TAA）的天然和疫苗诱导的免疫应答。在这里，我们发现Treg在小鼠前列腺老化转基因腺癌（TRAMP）雄性小鼠的肿瘤和肿瘤引流淋巴结中积累，这些小鼠自发地发展前列腺癌。TAA过表达和疾病进展也与TAA特异性耐受的诱导相关。在荷瘤小鼠的淋巴器官中发现TAA特异性T细胞。但是，它们已经失去了释放IFN-γ和杀死相关目标的能力。通过PC61单克隆抗体体内耗尽Treg，然后用抗原脉冲的树突状细胞重复接种，也不是用吲哚胺2，3-氧合酶的1-甲基-L-色氨酸抑制剂、PC61抗体和树突状细胞接种的组合治疗恢复了TAA特异性免疫应答。Treg似乎也不控制耐受诱导的早期阶段。事实上，从TRAMP小鼠尚未耐受的年龄第6周开始并延长至第12周的Treg耗竭并未避免耐受诱导。在TRAMP和野生型动物中，在引流树突状细胞接种部位的淋巴结中发现了类似的Treg积累。因此，我们得出结论，Treg积累是持续免疫应答部位的常见现象，特别是在TRAMP小鼠中，Treg可诱导肿瘤特异性耐受。
CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg) are thought to suppress the natural and vaccine-induced immune response against tumor-associated antigens (TAA). Here, we show that Treg accumulate in tumors and tumor-draining lymph nodes of aging transgenic adenocarcinoma of the mouse prostate (TRAMP) male mice, which spontaneously develop prostate cancer. TAA overexpression and disease progression associate also with induction of TAA-specific tolerance. TAA-specific T cells were found in the lymphoid organs of tumor-bearing mice. However, they had lost the ability to release IFN-gamma and kill relevant targets. Neither in vivo depletion of Treg by PC61 monoclonal antibody followed by repeated vaccinations with antigen-pulsed dendritic cells nor the combined treatment with 1-methyl-L-tryptophan inhibitor of the enzyme indoleamine 2,3-dyoxigenase, PC61 antibody, and dendritic cell vaccination restored the TAA-specific immune response. Treg did not seem to control the early phases of tolerance induction, as well. Indeed, depletion of Treg, starting at week 6, the age at which TRAMP mice are not yet tolerant, and prolonged up to week 12, did not avoid tolerance induction. A similar accumulation of Treg was found in the lymph nodes draining the site of dendritic cell vaccination both in TRAMP and wild-type animals. Hence, we conclude that Treg accrual is a phenomenon common to the sites of an ongoing immune response, and in TRAMP mice in particular, Treg are dispensable for induction of tumor-specific tolerance.