Relevance of Foxp3+ regulatory T cells for early and late phases of murine sepsis
Relevance of Foxp3+ regulatory T cells for early and late phases of murine sepsis
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DOI：
10.1111/imm.12490
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发表时间：
2015-09-01
期刊：
影响因子：
6.4
通讯作者：
Kehrmann, Jan
中科院分区：
文献类型：
--
作者：
Tatura, Roman;Zeschnigk, Michael;Kehrmann, Jan
Foxp3(+) 调节性 T (Treg) 细胞在脓毒症早期高炎症和随后的低炎症阶段中的作用尚不明确。据报道，Nrp1 表达可区分天然 Treg 细胞和诱导 Treg 细胞，但 Treg 细胞稳定性取决于 Foxp3-TSDR 的甲基化状态。为了具体评估 Foxp3(+) Treg 细胞在脓毒症早期和晚期中的作用，我们在 DEREG（调节性 T 细胞耗尽）小鼠模型中通过盲肠结扎和穿刺以及随后的铜绿假单胞菌肺部感染诱导脓毒症。我们发现小鼠败血症期间 Foxp3(+) Treg 细胞相对于所有 CD4(+) T 细胞均有所增加。使用新的甲基化敏感的定量RT-PCR方法和深度扩增子测序，我们证明天然的(Nrp1(+)Foxp3(+)) Treg细胞和大多数诱导的(Nrp1(-)Foxp3(+)) Treg细胞是稳定的并表现出未甲基化的foxp3-TSDR，并且这两种Treg细胞在健康和脓毒症小鼠中都具有功能抑制性。在早期脓毒症中，去除 Foxp3(+) Treg 细胞的 DEREG 小鼠比未去除 Foxp3(+) Treg 细胞的 DEREG 小鼠表现出更高的疾病评分、死亡率和白细胞介素 6 表达水平，这一发现表明 Foxp3(+) Treg 细胞限制了高炎症反应并加速恢复。盲肠结扎和穿刺后 1 周，铜绿假单胞菌继发感染前的 Treg 细胞耗竭不会影响细胞因子水平或继发感染的过程。然而，我们在 DEREG 小鼠继发感染期间观察到的中度 Treg 细胞复发可能会干扰这些结果。总之，Treg 细胞有助于早期脓毒症后的积极结果，但数据并不支持 Treg 细胞在晚期脓毒症期间免疫麻痹中的重要作用。
The role of Foxp3(+) regulatory T (Treg) cells in the course of the early hyper-inflammatory and subsequent hypo-inflammatory phases of sepsis is ambiguous. Whereas Nrp1 expression has been reported to discriminate natural Treg cells from induced Treg cells, the Treg cell stability depends on the methylation status of foxp3-TSDR. To specifically evaluate the role of Foxp3(+) Treg cells in the early and late phases of sepsis, we induced sepsis by caecal ligation and puncture and subsequent Pseudomonas aeruginosa lung infection in a DEREG (DEpletion of REGulatory T cells) mouse model. We found an increase of Foxp3(+) Treg cells to all CD4(+) T cells during murine sepsis. Using a new methylation-sensitive quantitative RT-PCR method and deep amplicon sequencing, we demonstrated that natural (Nrp1(+)Foxp3(+)) Treg cells and most induced (Nrp1(-)Foxp3(+)) Treg cells are stable and exhibit unmethylated foxp3-TSDR, and that both Treg populations are functionally suppressive in healthy and septic mice. DEREG mice depleted of Foxp3(+) Treg cells exhibit higher disease scores, mortality rates and interleukin-6 expression levels than do non-depleted DEREG mice in early-phase sepsis, a finding indicating that Foxp3(+) Treg cells limit the hyper-inflammatory response and accelerate recovery. Treg cell depletion before secondary infection with P.aeruginosa 1week after caecal ligation and puncture does not influence cytokine levels or the course of secondary infection. However, a moderate Treg cell recurrence, which we observed in DEREG mice during secondary infection, may interfere with these results. In summary, Treg cells contribute to a positive outcome after early-phase sepsis, but the data do not support a significant role of Treg cells in immune paralysis during late-phase sepsis.