TLR9 regulates the mycobacteria-elicited pulmonary granulomatous immune response in mice through DC-derived Notch ligand delta-like 4.
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-Guérin-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.
Ito
Toshihiro
T
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109-2200, USA.
Schaller
Matthew
M
Hogaboam
Cory M
CM
Standiford
Theodore J
TJ
Sandor
Matyas
M
Lukacs
Nicholas W
NW
Chensue
Stephen W
SW
Kunkel
Steven L
SL
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002135:Calcium-Binding Proteins; D002465:Cell Movement / Q000502:physiology; D003713:Dendritic Cells / Q000276:immunology*; D015769:Granuloma, Respiratory Tract / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009161:Mycobacterium / Q000276:immunology* / Q000472:pathogenicity; D009164:Mycobacterium Infections / Q000276:immunology / Q000473:pathology; D010641:Phenotype; D051880:Receptors, Notch / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C519665:DLL4 protein, mouse; D020381:Interleukin-17; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins; D051880:Receptors, Notch; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D007371:Interferon-gamma