Department of Pathology, University of Michigan, Ann Arbor, MI 48105, USA.
Eur J Immunol. 2010 Apr;40(4):998-1010. doi: 10.1002/eji.200939739.
Immunosuppression following severe sepsis remains a significant human health concern, as long-term morbidity and mortality rates of patients who have recovered from life-threatening septic shock remain poor. Mouse models of severe sepsis indicate this immunosuppression may be partly due to alterations in myeloid cell function; however, the effect of severe sepsis on subsequent CD4(+) T-cell responses remains unclear. In the present study, CD4(+) T cells from mice subjected to an experimental model of severe sepsis (cecal ligation and puncture (CLP)) were analyzed in vitro. CD4(+)CD62L(+) T cells from CLP mice exhibited reduced proliferative capacity and altered gene expression. Additionally, CD4(+)CD62L(+) T cells from CLP mice exhibit dysregulated cytokine production after in vitro skewing with exogenous cytokines, indicating a decreased capability of these cells to commit to either the T(H)1 or T(H)2 lineage. Repressive histone methylation marks were also evident at promoter regions for the T(H)1 cytokine IFN-gamma and the T(H)2 transcription factor GATA-3 in naïve CD4(+) T cells from CLP mice. These results provide evidence that CD4(+) T-cell subsets from post-septic mice exhibit defects in activation and effector function, possibly due to chromatin remodeling proximal to genes involved in cytokine production or gene transcription.
严重脓毒症后的免疫抑制仍然是一个重大的人类健康问题，因为从威胁生命的感染性休克中恢复过来的患者的长期发病率和死亡率仍然很差。严重脓毒症的小鼠模型表明，这种免疫抑制可能部分是由于髓样细胞功能的改变；然而，严重脓毒症对随后的 CD4(+)T 细胞反应的影响仍不清楚。在本研究中，分析了经历严重脓毒症实验模型（盲肠结扎和穿孔（CLP））的小鼠的 CD4(+)T 细胞。CLP 小鼠的 CD4(+)CD62L(+)T 细胞表现出增殖能力降低和基因表达改变。此外，CLP 小鼠的 CD4(+)CD62L(+)T 细胞在体外用外源性细胞因子偏向后表现出失调的细胞因子产生，表明这些细胞向 T(H)1 或 T(H)2 谱系的定向能力降低。在 CLP 小鼠的幼稚 CD4(+)T 细胞中，T(H)1 细胞因子 IFN-γ和 T(H)2 转录因子 GATA-3 的启动子区域也存在明显的抑制性组蛋白甲基化标记。这些结果提供了证据，表明来自脓毒症后小鼠的 CD4(+)T 细胞亚群在激活和效应功能方面存在缺陷，这可能是由于与细胞因子产生或基因转录相关的基因附近的染色质重塑。
