OX40 costimulation can abrogate Foxp3+ regulatory T cell-mediated suppression of antitumor immunity.
OX40 costimulation can abrogate Foxp3+ regulatory T cell-mediated suppression of antitumor immunity.
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DOI：
10.1002/ijc.24435
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发表时间：
2009-08-01
影响因子：
6.4
通讯作者：
Tani T
中科院分区：
文献类型：
--
作者：
Kitamura N;Murata S;Ueki T;Mekata E;Reilly RT;Jaffee EM;Tani T
调节性T细胞在维持免疫耐受中起着重要作用，而免疫耐受是提高抗肿瘤免疫力需要克服的主要障碍之一。最近，Treg被证明结构性地表达OX40(CD134)，它是肿瘤坏死因子受体家族的成员，在TCR触发后瞬时表达在效应T细胞上，并通过它促进效应T细胞的增殖和记忆T细胞的发育。然而，关于OX40对Tregs的协同刺激在肿瘤免疫学中的作用还知之甚少。在这里，我们展示了OX40信号在体外和体内调节自然产生的Tregs的功能。OX40共刺激可降低Tregs上Foxp3的表达，但IL-2刺激不能降低Foxp3表达。Tregs可抑制TcR激活后的−T细胞的增殖，而OX40共刺激的Tregs可逆转这一抑制作用。此外，Tregs还能抑制TCR激活后的CD4+T细胞和CD8+T细胞的增殖，但与OX40共刺激的Tregs则失去抑制作用。有趣的是，Tregs在Ag再刺激后对抗原特异性CD8+T细胞的增殖或细胞因子的分泌有最小的抑制作用。此外，在体内，Tregs对抗肿瘤作用的抑制作用被OX40共刺激逆转。我们的数据表明，除了控制效应T细胞的功能外，OX40共刺激直接控制Treg介导的肿瘤免疫抑制。
Regulatory T cells (Tregs) play an important role in maintaining immunological tolerance that is one of the main obstacles to overcome for improving antitumor immunity. Recently, the Treg has been shown to constitutively express OX40 (CD134), which is a member of the TNF receptor family that is transiently expressed on effector T cells after TCR triggering, and through which the signal enhances effector T cell proliferation and memory T cell development. However, little is known about the role of OX40 costimulation to Tregs in tumor immunology. Here we show that OX40 signaling modulates the function of naturally occurring Tregs in vitro and in vivo. Foxp3 expression on Tregs was reduced by OX40 costimulation, but not by IL-2 stimulation. Tregs suppressed the proliferation of naïve CD4+ CD25− T cells after TCR triggering, in contrast, OX40 costimulated Tregs that reduced Foxp3 expression reversed the suppressive function. In addition, Tregs inhibited the proliferation of TCR stimulated (primed) CD4+ T cells and naïve CD8+ T cells after TCR-mediated activation, however, Tregs with OX40 costimulation lost their suppressive function. Interestingly, Tregs minimally suppressed the proliferation or the cytokine secreting of Ag-specific CD8+ T cells after Ag-restimulation. Furthermore, Tregs suppressive function to the antitumor effect was reversed by OX40 costimulation in vivo. Our data indicate that, in addition to controlling effector T cell function, OX40 costimulation directly controls Treg-mediated suppression in tumor immunity.
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DOI：
10.1084/jem.20042167
发表时间：
2005-05-16
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Ercolini AM;Ladle BH;Manning EA;Pfannenstiel LW;Armstrong TD;Machiels JP;Bieler JG;Emens LA;Reilly RT;Jaffee EM
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Jaffee EM
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影响因子：
15.3
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通讯作者：
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影响因子：
56.9
作者：
Pasare, C;Medzhitov, R
通讯作者：
Medzhitov, R
影响因子：
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作者：
Peng, GY;Guo, Z;Wang, RF
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影响因子：
15.3
作者：
Ko, K;Yamazaki, S;Nakamura, K;Nishioka, T;Hirota, K;Yamaguchi, T;Shimizu, J;Nomura, T;Chiba, T;Sakaguchi, S
通讯作者：
Sakaguchi, S