TLR9 regulates the mycobacteria-elicited pulmonary granulomatous immune response in mice through DC-derived Notch ligand delta-like 4
TLR9 regulates the mycobacteria-elicited pulmonary granulomatous immune response in mice through DC-derived Notch ligand delta-like 4
复制标题
DOI：
10.1172/jci35647
复制
发表时间：
2009-01-01
影响因子：
15.9
通讯作者：
Kunkel, Steven L.
中科院分区：
文献类型：
--
作者：
Ito, Toshihiro;Schaller, Matthew;Kunkel, Steven L.
TLR9活化对于维持分枝杆菌引起的肺肉芽肿反应是重要的，这是分枝杆菌感染后保护性免疫反应的标志。然而，TLR9的这种作用的潜在机制尚不清楚。在这里，我们表明，Tlr9缺陷小鼠与分枝杆菌抗原的挑战显示改变的Th17细胞因子谱，减少肉芽肿相关的髓样树突状细胞的积累，和深刻受损的δ样4（dll4）Notch配体的表达。机制分析显示，WT骨髓来源的DC而不是巨噬细胞促进Th17细胞从卡介苗攻击的（BCG攻击的）肺CD4（+）T细胞分化。与从WT小鼠分离的相同细胞相比，从接种分枝杆菌抗原的Tlr9缺陷小鼠分离的肺和骨髓DC表达更低水平的dll4 Notch配体。在肉芽肿形成过程中，用dll4特异性中和抗体被动免疫WT小鼠，导致肉芽肿更大，Th17相关细胞因子水平更低。此外，dll4在体外特异性调节Th17活化。总之，这些结果表明dll4在分枝杆菌攻击期间在促进Th17效应子活性中起重要作用。此外，TLR9似乎是最佳dll4表达和分枝杆菌抗原诱导的小鼠肉芽肿形成的调节所需的。
TLR9 activation is important for the maintenance of mycobacteria-elicited pulmonary granulomatous responses, hallmarks of protective immune responses following mycobacterial infection. However, the mechanism or mechanisms underlying this effect of TLR9 are not clear. Here, we show that Tlr9-deficient mice challenged with a Mycobacterium antigen display an altered Th17 cytokine profile, decreased accumulation of granuloma-associated myeloid DCs, and profoundly impaired delta-like 4 (dll4) Notch ligand expression. Mechanistic analysis revealed that WT bone marrow-derived DCs but not macrophages promoted the differentiation of Th17 cells from bacillus Calmette-Guerin-challenged (BCG-challenged) lung CD4(+) T cells. Both lung and bone marrow DCs isolated from Tlr9-deficient mice inoculated with Mycobacterium antigen expressed lower levels of dll4 Notch ligand than the same cells isolated from WT mice. Passively immunizing WT mice with neutralizing antibodies specific for dll4 during granuloma formation resulted in larger granulomas and lower levels of Th17-related cytokines. In addition, dll4 specifically regulated Th17 activation in vitro. Together, these results suggest dll4 plays an important role in promoting Th17 effector activity during a mycobacterial challenge. Furthermore, TLR9 seems to be required for optimal dll4 expression and the regulation of Mycobacterium antigen-elicited granuloma formation in mice.