CD4+T cells mediate abscess formation in intra-abdominal sepsis by an IL-17-dependent mechanism
CD4+T cells mediate abscess formation in intra-abdominal sepsis by an IL-17-dependent mechanism
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DOI：
10.4049/jimmunol.170.4.1958
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发表时间：
2003-02-15
影响因子：
4.4
通讯作者：
Tzianabos, AO
中科院分区：
文献类型：
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作者：
Chung, DR;Kasper, DL;Tzianabos, AO
与腹腔内脓毒症相关的脓肿形成会导致严重的发病情况，甚至可能致命。先前的研究表明T细胞参与了脓肿形成的发病机制，我们最近发现，被来自诸如金黄色葡萄球菌和脆弱拟杆菌等致脓肿细菌的两性离子荚膜多糖在体外激活的CD4(+) T细胞，在转移到未免疫的大鼠体内时会引发这种宿主反应。在这项研究中，我们发现与CD8(-/-)或野生型动物相比，缺乏含αβTCR的T细胞或CD4(+) T细胞的小鼠在受到脆弱拟杆菌或致脓肿两性离子多糖攻击后不会形成脓肿。将野生型小鼠的CD4(+) T细胞转移到αβTCR(-/-)动物体内可恢复这种能力。脓肿的诱导需要通过CD28 - B7途径对T细胞进行共刺激，并且用STAT4(-/-)和STAT6(-/-)小鼠进行的T细胞转移实验表明，这种宿主反应依赖于STAT4信号传导。几乎完全由活化的CD4(+) T细胞产生的促炎细胞因子白细胞介素 - 17（IL - 17）的水平在Th2受损（STAT6(-/-)）小鼠中与脓肿形成显著相关，而STAT4(-/-)小鼠的这种细胞因子水平明显低于对照动物。在细菌攻击后24小时，腹腔内活化的CD4(+) T细胞数量增加，随后出现脓肿形成。共聚焦激光扫描显微镜分析显示，在这些动物中CD4(+) T细胞构成脓肿壁并在该部位产生IL - 17。给予针对IL - 17的中和抗体可阻止小鼠在细菌攻击后形成脓肿。这些数据描述了腹腔内脓肿形成所必需的特定T细胞反应，并强调了IL - 17在这一疾病过程中的作用。
Abscess formation associated with intra-abdominal sepsis causes severe morbidity and can be fatal. Previous studies have implicated T cells in the pathogenesis of abscess formation, and we have recently shown that CD4(+) T cells activated in vitro by zwitterionic capsular polysaccharides from abscess-inducing bacteria such as Staphylococcus aureus and Bacteroides fragilis initiate this host response when transferred to naive rats. In this study, we show that mice deficient in alphabetaTCR-bearing T cells or CD4(+) T cells fail to develop abscesses following challenge with B. fragilis or abscess-inducing zwitterionic polysaccharides, compared with CD8(-/-) or wild-type animals. Transfer of CD4(+) T cells from wild-type mice to alphabetaTCR(-/-) animals reconstituted this ability. The induction of abscesses required T cell costimulation via the CD28-B7 pathway, and T cell transfer experiments with STAT4(-/-) and STAT6(-/-) mice demonstrated that this host response is dependent on STAT4 signaling. Significantly higher levels of IL-17, a proinflammatory cytokine produced almost exclusively by activated CD4(+) T cells, were associated with abscess formation in Th2-impaired (STAT6(-/-)) mice, while STAT4(-/-) mice had significantly lower levels of this cytokine than control animals. The formation of abscesses was preceded by an increase in the number of activated CD4(+) T cells in the peritoneal cavity 24 h following bacterial challenge. Confocal laser-scanning microscopy analysis revealed that CD4(+) T cells comprise the abscess wall in these animals and produce IL-17 at this site. Administration of a neutralizing Ab specific for IL-17 prevented abscess formation following bacterial challenge in mice. These data delineate the specific T cell response necessary for the development of intra-abdominal abscesses and underscore the role of IL-17 in this disease process.