Tyk2-signaling plays an important role in host defense against Escherichia coli through IL-23-induced IL-17 production by gammadelta T cells.
Tyk2-signaling plays an important role in host defense against Escherichia coli through IL-23-induced IL-17 production by gammadelta T cells.
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发表时间：
2008
影响因子：
4.4
通讯作者：
R. Nakamura;K. Shibata;H. Yamada;K. Shimoda;K. Nakayama;Y. Yoshikai
中科院分区：
文献类型：
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作者：
R. Nakamura;K. Shibata;H. Yamada;K. Shimoda;K. Nakayama;Y. Yoshikai
酪氨酸激酶2(TYK2)是JAK信号转导家族的一员，参与包括IL-23在内的多种细胞因子触发的细胞内信号转导。我们最近报道了幼鼠腹膜腔内常驻的Gammadelta T细胞产生IL-17，以响应IL-23。在这项研究中，我们利用TYK2缺陷(-/-)小鼠研究了TYK2介导的信号在Gammadelta T细胞产生IL-17中的重要性。TYK2(-/-)小鼠腹膜腔内的Gammadelta T细胞表现出与TYK2(+/+)小鼠相似的效应/记忆表型和TCRV谱，并在PMA和离子霉素的作用下产生与TYK2(+/+)小鼠相当的IL-17水平，表明在没有TYK2信号转导的情况下，正常分化为产生IL-17的效应细胞。然而，TYK2(-/-)小鼠的Gammadelta T细胞在体外对IL-23的反应比TYK2(+/+)小鼠产生的IL-17要少。同样，TYK2(-/-)小鼠腹腔内的Gammadelta T细胞在ip后显示IL-17的产生严重受损。感染大肠杆菌，尽管TYK2(+/+)小鼠产生的IL-23水平与TYK2(+/+)小鼠相当。结果，TYK2(-/-)小鼠在感染大肠杆菌后，中性粒细胞的渗透减少，细菌清除严重受损。这些结果表明，TYK2信号在IL-23诱导的Gammadelta T细胞产生IL-17过程中起关键作用，而Gammadelta T细胞通过控制中性粒细胞介导的免疫反应参与宿主防御的第一线。
Tyrosine kinase 2 (Tyk2), a member of the JAK-signal transducer family, is involved in intracellular signaling triggered by various cytokines, including IL-23. We have recently reported that resident gammadelta T cells in the peritoneal cavity of naive mice produced IL-17 in response to IL-23. In this study, we examined importance of Tyk2-mediated signaling in the IL-17 production by gammadelta T cells using Tyk2 deficient (-/-) mice. Gammadelta T cells in the peritoneal cavity of Tyk2(-/-) mice displayed effecter/memory phenotypes and TCR V repertoire similar to those in Tyk2(+/+) mice and produced comparable level of IL-17 to those in Tyk2(+/+) mice in response to PMA and ionomycin, indicating normal differentiation to IL-17-producing effectors in the absence of Tyk2-signaling. However, gammadelta T cells in Tyk2(-/-) mice produced less amount of IL-17 in response to IL-23 in vitro than those in Tyk2(+/+) mice. Similarly, gammadelta T cells in the peritoneal cavity of Tyk2(-/-) mice showed severely impaired IL-17 production after an i.p. infection with E. coli despite comparable level of IL-23 production to Tyk2(+/+) mice. As a consequence, Tyk2(-/-) mice showed a reduced infiltration of neutrophils and severely impaired bacterial clearance after Escherichia coli infection. These results indicate that Tyk2-signaling is critical for IL-23-induced IL-17 production by gammadelta T cells, which is involved in the first line of host defense by controlling neutrophil-mediated immune responses.