Dendritic cells during polymicrobial sepsis rapidly mature but fail to initiate a protective Th1-type immune response
Dendritic cells during polymicrobial sepsis rapidly mature but fail to initiate a protective Th1-type immune response
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DOI：
10.1189/jlb.0705413
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发表时间：
2006-03-01
影响因子：
5.5
通讯作者：
Schade, F. Ulrich
中科院分区：
文献类型：
--
作者：
Flohe, Stefanie B.;Agrawal, Hemant;Schade, F. Ulrich
多菌败血症与以抗炎介质为主的免疫抑制和细胞凋亡导致的淋巴细胞大量丢失有关。树突状细胞(DC)是一种强大的抗原提呈细胞，在T细胞活化中起关键作用。我们在小鼠盲肠结扎和穿孔(CLP)模型中验证了DC参与脓毒症介导的免疫抑制的假设，该模型类似于人类多菌败血症。在CLP后不同时间点，取脾和外周淋巴结来源的DC，从共刺激分子表达、细胞因子合成和亚群组成等方面进行特征分析。CLP后8h，脾树突状细胞CD86、CD40表达增强，而CD80表达不明显。相反，淋巴结DC同样增加了CD86、CD40和CD80的表达。然而，这种成熟过程在淋巴结中比在脾中发生得晚。脓毒症小鼠的脾DC即使在CpG或脂多糖+CD40配体的刺激下也不能分泌IL-12，但与对照小鼠的DC相比，释放出更高水平的IL-10。中和内源性IL-10不能恢复脓毒症小鼠DC分泌IL-12。此外，在脓毒症期间，脾中的CD4(+)CD8(-)和CD4(-)CD8(+)亚群丢失，剩余的DC表现出与IL-2合成减少相关的同种异体T细胞激活能力降低。因此，在脓毒症期间，脾DC对细菌刺激获得异常反应状态，并且选择性地丢失了两种DC亚型。这些变化发生在。P-DC的行为可能与败血症时宿主对细菌的反应受损有关。
Polymicrobial sepsis is associated with immunosuppression caused by the predominance of anti-inflammatory mediators and profound loss of lymphocytes through apoptosis. Dendritic cells (DC) are potent antigen-presenting cells and play a key role in T cell activation. We tested the hypothesis that DC are involved in sepsis-mediated immunosuppression in a mouse cecal ligation and puncture (CLP) model, which resembles human polymicrobial sepsis. At different time-points after CLP, DC from the spleen and peripheral lymph nodes were characterized in terms of expression of costimulatory molecules, cytokine synthesis, and subset composition. Splenic DC strongly up-regulated CD86 and CD40 but not CD80 as soon as 8 h after CLP. In contrast, lymph node DC equally increased the expression of CD86, CD40, and CD80. However, this process of maturation occurred later in the lymph nodes than in the spleen. Splenic DC from septic mice were unable to secrete interleukin (IL)-12, even upon stimulation with CpG or lipopolysaccharide + CD40 ligand, but released high levels of IL-10 in comparison to DC from control mice. Neutralization of endogenous IL-10 could not restore IL-12 secretion by DC of septic mice. In addition, the splenic CD4(+)CD8(-) and CD4(-)CD8(+) subpopulations were lost during sepsis, and the remaining DC showed a reduced capacity for allogeneic T cell activation associated with decreased IL-2 synthesis. Thus, during sepsis, splenic DC acquire a state of aberrant responsiveness to bacterial stimuli, and two DC subtypes are selectively lost. These changes in. p DC behavior might contribute to impaired host response against bacteria during sepsis.