The post sepsis-induced expansion and enhanced function of regulatory T cells create an environment to potentiate tumor growth
The post sepsis-induced expansion and enhanced function of regulatory T cells create an environment to potentiate tumor growth
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DOI：
10.1182/blood-2009-09-241083
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发表时间：
2010-06-03
期刊：
影响因子：
20.3
通讯作者：
Kunkel, Steven L.
中科院分区：
文献类型：
--
作者：
Cavassani, Karen A.;Carson, William F.;Kunkel, Steven L.
严重脓毒症患者的一个更隐蔽的结果是严重的免疫抑制。在这项研究中，我们解决了脓毒症后免疫缺陷的假设，部分原因是由于调节性T细胞（T细胞）的存在和/或扩增。在从严重脓毒症中恢复后，小鼠表现出显著更高数量的TcR，其与对照相比发挥更大的体外抑制活性。T细胞的扩增并不局限于CD 25（+）细胞，因为在脓毒症后小鼠的CD 25（-）细胞中也检测到Foxp 3表达。后一组在Foxp 3启动子处表现出染色质重塑的显著增加，因为H3 K9处乙酰化的显著增加与Foxp 3转录的增加相关。脓毒症后脾树突状细胞促进Treg的体外转化。使用实体瘤模型来探索TdR在体内环境中的功能，我们发现脓毒症后的小鼠与具有同基因肿瘤模型的假治疗小鼠相比显示出肿瘤生长的增加。这一观察结果可能与脓毒症后T细胞损伤CD 8（+）T细胞介导的抗肿瘤反应的能力有关。总之，这些数据表明脓毒症后免疫系统部分地通过增强的Treg扩增和功能阻碍肿瘤免疫监视。（血。2010; 115（22）：4403-4411）
One of the more insidious outcomes of patients who survive severe sepsis is profound immunosuppression. In this study, we addressed the hypothesis that post septic immune defects were due, in part, to the presence and/or expansion of regulatory T cells (Tregs). After recovery from severe sepsis, mice exhibited significantly higher numbers of Tregs, which exerted greater in vitro suppressive activity compared with controls. The expansion of Tregs was not limited to CD25(+) cells, because Foxp3 expression was also detected in CD25(-) cells from post septic mice. This latter group exhibited a significant increase of chromatin remodeling at the Foxp3 promoter, because a marked increase in acetylation at H3K9 was associated with an increase in Foxp3 transcription. Post septic splenic dendritic cells promoted Treg conversion in vitro. Using a solid tumor model to explore the function of Tregs in an in vivo setting, we found post septic mice showed an increase in tumor growth compared with sham-treated mice with a syngeneic tumor model. This observation could mechanistically be related to the ability of post septic Tregs to impair the antitumor response mediated by CD8(+) T cells. Together, these data show that the post septic immune system obstructs tumor immunosurveillance, in part, by augmented Treg expansion and function. (Blood. 2010; 115(22): 4403-4411)