IL-21-mediated Foxp3 suppression leads to enhanced generation of antigen-specific CD8+ cytotoxic T lymphocytes
IL-21-mediated Foxp3 suppression leads to enhanced generation of antigen-specific CD8+ cytotoxic T lymphocytes
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DOI：
10.1182/blood-2007-05-089375
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发表时间：
2008-01-01
期刊：
影响因子：
20.3
通讯作者：
Yee, Cassian
中科院分区：
文献类型：
--
作者：
Li, Yongqing;Yee, Cassian
通过去除免疫调节障碍，将有助于从患者中可重复地分离肿瘤抗原特异性T细胞。使用人类模型引发T细胞对肿瘤相关抗原的反应，我们开发了一种新的策略，通过CD 25耗竭和IL-21治疗的组合消除了几乎所有的Foxp 3表达细胞，导致Foxp 3（+）细胞减少150倍以上至几乎检测不到的水平，抗原特异性细胞毒性T淋巴细胞（CTL）增加200倍以上。本研究中显示的Foxp 3消除的程度和抗原特异性CTL的扩增程度以前无法实现，并且是IL-21所特有的。我们首次证明了IL-21介导的抗原特异性CTL扩增的可能机制，该机制涉及Foxp 3表达细胞的抑制和体外肿瘤相关抗原特异性CTL产生的抑制逆转。总之，CD 25耗竭和IL-21暴露的组合通过释放调节约束导致显著增强的CTL诱导，并且代表了用于过继性细胞治疗的抗原特异性T细胞的离体产生的稳健策略。
Efforts to reproducibly isolate tumor antigen-specific T cells from patients would be facilitated by removing immunoregulatory barriers. Using a human model for eliciting T-cell responses to tumor-associated antigens, we develop a novel strategy that eliminates nearly all Foxp3-expressing cells through the combination of CD25 depletion and IL-21 treatment resulting in a more than 150-fold decrease in Foxp3(+) cells to virtually undetectable levels and a more than 200-fold increase in antigen-specific cytotoxic T lymphocytes (CTLs). The extent of Foxp3 elimination and degree of expansion of antigen-specific CTLs shown in this study have not previously been achievable and are unique to IL-21. We demonstrate for the first time a possible mechanism for IL-21-mediated expansion of antigen-specific CTLs that involves suppression of Foxp3-expressing cells and reversal of inhibition to tumor-associated antigen-specific CTL generation in vitro. Taken together, the combination of CD25 depletion and IL-21 exposure, by releasing regulatory constraints, leads to markedly enhanced CTL induction and represents a robust strategy for the ex vivo generation of antigen-specific T cells for adoptive cellular therapy.