Hölscher Christoph, Reiling Norbert, Schaible Ulrich E, Hölscher Alexandra, Bathmann Clara, Korbel Daniel, Lenz Insa, Sonntag Tanja, Kröger Svenja, Akira Shizuo, Mossmann Horst, Kirschning Carsten J, Wagner Hermann, Freudenberg Marina, Ehlers Stefan
Junior Research Group Molecular Infection Biology, Research Center Borstel, Borstel, Germany.
Eur J Immunol. 2008 Mar;38(3):680-94. doi: 10.1002/eji.200736458.
The role of Toll-like receptors (TLR) and MyD88 for immune responses to Mycobacterium tuberculosis (Mtb) infection remains controversial. To address the impact of TLR-mediated pathogen recognition and MyD88-dependent signaling events on anti-mycobacterial host responses, we analyzed the outcome of Mtb infection in TLR2/4/9 triple- and MyD88-deficient mice. After aerosol infection, both TLR2/4/9-deficient and wild-type mice expressed pro-inflammatory cytokines promoting antigen-specific T cells and the production of IFN-gamma to similar extents. Moreover, TLR2/4/9-deficient mice expressed IFN-gamma-dependent inducible nitric oxide synthase and LRG-47 in infected lungs. MyD88-deficient mice expressed pro-inflammatory cytokines and were shown to expand IFN-gamma-producing antigen-specific T cells, albeit in a delayed fashion. Only mice that were deficient for MyD88 rapidly succumbed to unrestrained mycobacterial growth, whereas TLR2/4/9-deficient mice controlled Mtb replication. IFN-gamma-dependent restriction of mycobacterial growth was severely impaired only in Mtb-infected MyD88, but not in TLR2/4/9-deficient bone marrow-derived macrophages. Our results demonstrate that after Mtb infection neither TLR2, -4, and -9, nor MyD88 are required for the induction of adaptive T cell responses. Rather, MyD88, but not TLR2, TLR4 and TLR9, is critical for triggering macrophage effector mechanisms central to anti-mycobacterial defense.
Toll样受体（TLR）和髓样分化因子88（MyD88）在结核分枝杆菌（Mtb）感染免疫反应中的作用仍存在争议。为了探讨TLR介导的病原体识别和MyD88依赖性信号事件对抗分枝杆菌宿主反应的影响，我们分析了TLR2/4/9三联体缺陷和MyD88缺陷小鼠中Mtb感染的结果。气溶胶感染后，TLR2/4/9缺陷小鼠和野生型小鼠均表达促炎细胞因子，促进抗原特异性T细胞并在相似程度上产生γ干扰素。此外，TLR2/4/9缺陷小鼠在感染的肺中表达γ干扰素依赖性诱导型一氧化氮合酶和LRG-47。MyD88缺陷小鼠表达促炎细胞因子，并显示出产生γ干扰素的抗原特异性T细胞扩增，尽管有所延迟。只有MyD88缺陷的小鼠迅速死于不受控制的分枝杆菌生长，而TLR2/4/9缺陷小鼠则能控制Mtb复制。γ干扰素依赖性的分枝杆菌生长限制仅在感染Mtb的MyD88缺陷小鼠中严重受损，而在TLR2/4/9缺陷的骨髓来源巨噬细胞中则未受损。我们的结果表明，Mtb感染后，诱导适应性T细胞反应既不需要TLR2、-4和-9，也不需要MyD88。相反，MyD88而非TLR2、TLR4和TLR9对于触发抗分枝杆菌防御核心的巨噬细胞效应机制至关重要。
