Murphy Thomas J, Ni Choileain Niamh, Zang Yan, Mannick John A, Lederer James A
Department of Surgery (Immunology), Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
J Immunol. 2005 Mar 1;174(5):2957-63. doi: 10.4049/jimmunol.174.5.2957.
Major injury initiates a systemic inflammatory response that can be detrimental to the host. We have recently reported that burn injury primes innate immune cells for a progressive increase in TLR4 and TLR2 agonist-induced proinflammatory cytokine production and that this inflammatory phenotype is exaggerated in adaptive immune system-deficient (Rag1(-/-)) mice. The present study uses a series of adoptive transfer experiments to determine which adaptive immune cell type(s) has the capacity to control innate inflammatory responses after injury. We first compared the relative changes in TLR4- and TLR2-induced TNF-alpha, IL-1beta, and IL-6 production by spleen cell populations prepared from wild-type (WT), Rag1(-/-), CD4(-/-), or CD8(-/-) mice 7 days after sham or burn injury. Our findings indicated that splenocytes prepared from burn-injured CD8(-/-) mice displayed TLR-induced cytokine production levels similar to those in WT mice. In contrast, spleen cells from burn-injured CD4(-/-) mice produced cytokines at significantly higher levels, equivalent to those in Rag1(-/-) mice. Moreover, reconstitution of Rag1(-/-) or CD4(-/-) mice with WT CD4(+) T cells reduced postinjury cytokine production to WT levels. Additional separation of CD4(+) T cells into CD4(+)CD25(+) and CD4(+)CD25(-) subpopulations before their adoptive transfer into Rag1(-/-) mice showed that CD4(+)CD25(+) T cells were capable of reducing TLR-stimulated cytokine production levels to WT levels, whereas CD4(+)CD25(-) T cells had no regulatory effect. These findings suggest a previously unsuspected role for CD4(+)CD25(+) T regulatory cells in controlling host inflammatory responses after injury.
严重损伤会引发全身性炎症反应，这可能对宿主有害。我们最近报道，烧伤会使天然免疫细胞对Toll样受体4（TLR4）和Toll样受体2（TLR2）激动剂诱导的促炎细胞因子产生呈进行性增加，并且这种炎症表型在适应性免疫系统缺陷（Rag1基因敲除）小鼠中会被放大。本研究采用一系列过继转移实验来确定哪种适应性免疫细胞类型有能力控制损伤后的天然炎症反应。我们首先比较了假手术或烧伤7天后，从野生型（WT）、Rag1基因敲除、CD4基因敲除或CD8基因敲除小鼠制备的脾细胞群体中，TLR4和TLR2诱导的肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）和白细胞介素-6（IL-6）产生的相对变化。我们的研究结果表明，烧伤后的CD8基因敲除小鼠制备的脾细胞显示出与WT小鼠相似的TLR诱导的细胞因子产生水平。相比之下，烧伤后的CD4基因敲除小鼠的脾细胞产生细胞因子的水平显著更高，与Rag1基因敲除小鼠相当。此外，用WT CD4⁺ T细胞重建Rag1基因敲除或CD4基因敲除小鼠可将损伤后细胞因子产生降低到WT水平。在将CD4⁺ T细胞过继转移到Rag1基因敲除小鼠之前，将其进一步分离为CD4⁺CD25⁺和CD4⁺CD25⁻亚群，结果显示CD4⁺CD25⁺ T细胞能够将TLR刺激的细胞因子产生水平降低到WT水平，而CD4⁺CD25⁻ T细胞没有调节作用。这些发现提示CD4⁺CD25⁺调节性T细胞在控制损伤后宿主炎症反应中发挥了此前未被认识到的作用。
