Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA.
J Immunol. 2010 Apr 1;184(7):3755-67. doi: 10.4049/jimmunol.0902065. Epub 2010 Feb 22.
Recognition of intracellular bacteria by macrophages leads to secretion of type I IFNs. However, the role of type I IFN during bacterial infection is still poorly understood. Francisella tularensis, the causative agent of tularemia, is a pathogenic bacterium that replicates in the cytosol of macrophages leading to secretion of type I IFN. In this study, we investigated the role of type I IFNs in a mouse model of tularemia. Mice deficient for type I IFN receptor (IFNAR1(-/-)) are more resistant to intradermal infection with F. tularensis subspecies novicida (F. novicida). Increased resistance to infection was associated with a specific increase in IL-17A/F and a corresponding expansion of an IL-17A(+) gammadelta T cell population, indicating that type I IFNs negatively regulate the number of IL-17A(+) gammadelta T cells during infection. Furthermore, IL-17A-deficient mice contained fewer neutrophils compared with wild-type mice during infection, indicating that IL-17A contributes to neutrophil expansion during F. novicida infection. Accordingly, an increase in IL-17A in IFNAR1(-/-) mice correlated with an increase in splenic neutrophil numbers. Similar results were obtained in a mouse model of pneumonic tularemia using the highly virulent F. tularensis subspecies tularensis SchuS4 strain and in a mouse model of systemic Listeria monocytogenes infection. Our results indicate that the type I IFN-mediated negative regulation of IL-17A(+) gammadelta T cell expansion is conserved during bacterial infections. We propose that this newly described activity of type I IFN signaling might participate in the resistance of the IFNAR1(-/-) mice to infection with F. novicida and other intracellular bacteria.
巨噬细胞识别细胞内细菌会导致 I 型干扰素的分泌。然而，I 型干扰素在细菌感染中的作用仍知之甚少。土拉弗朗西斯菌（Francisella tularensis）是引起土拉热的病原体，它在巨噬细胞的细胞质中复制，导致 I 型干扰素的分泌。在这项研究中，我们研究了 I 型干扰素在土拉热小鼠模型中的作用。I 型干扰素受体（IFNAR1(-/-)）缺陷的小鼠对皮下感染土拉弗朗西斯菌亚种 novicida（F. novicida）更具抵抗力。对感染的抵抗力增加与 IL-17A/F 的特异性增加以及 IL-17A(+)γδ T 细胞群体的相应扩张有关，表明 I 型干扰素在感染过程中负调控 IL-17A(+)γδ T 细胞的数量。此外，与野生型小鼠相比，IL-17A 缺陷小鼠在感染期间中性粒细胞较少，表明 IL-17A 有助于 F. novicida 感染期间中性粒细胞的扩张。因此，IFNAR1(-/-)小鼠中 IL-17A 的增加与脾脏中性粒细胞数量的增加相关。在使用高度毒力的土拉弗朗西斯菌亚种 tularensis SchuS4 株的肺炎型土拉热小鼠模型和系统性李斯特菌感染的小鼠模型中获得了类似的结果。我们的结果表明，I 型干扰素介导的 IL-17A(+)γδ T 细胞扩张的负调控在细菌感染过程中是保守的。我们提出，I 型干扰素信号的这种新描述的活性可能参与了 IFNAR1(-/-)小鼠对 F. novicida 和其他细胞内细菌感染的抵抗。
