Toll-like receptor 6 drives differentiation of tolerogenic dendritic cells and contributes to LcrV-mediated plague pathogenesis.
Educating dendritic cells (DC) to become tolerogenic DC, which promote regulatory IL-10 immune responses, represents an effective immune evasion strategy for pathogens. Yersinia pestis virulence factor LcrV is reported to induce IL-10 production via interaction with Toll-like receptor (TLR) 2. However, TLR2-/- mice are not protected against subcutaneous plague infection. Using complementary in vitro and in vivo approaches and LcrV as a model, we show that TLR6 associates with TLR2 to induce tolerogenic DC and regulatory type-1 T cells selectively secreting IL-10. In contrast, TLR1 heterodimerizes with TLR2 to promote proinflammatory IL-12p40 cytokine, producing DC and inflammatory T cell differentiation. LcrV specifically hijacks the TLR2/6 pathway to stimulate IL-10 production, which blocks host protective inflammatory responses. These results explain why TLR2 can mediate both pro- and anti-inflammatory responses and identify TLR6 as a distinct receptor driving regulatory IL-10 responses.
Depaolo
R William
RW
Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
Tang
Fangming
F
Kim
Inyoung
I
Han
Mei
M
Levin
Nadine
N
Ciletti
Nancy
N
Lin
Anning
A
Anderson
Debra
D
Schneewind
Olaf
O
Jabri
Bana
B
D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology*; D002454:Cell Differentiation; D015169:Colony Count, Microbial; D003713:Dendritic Cells / Q000276:immunology*; D007155:Immunologic Factors / Q000494:pharmacology*; D016753:Interleukin-10 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010930:Plague / Q000276:immunology* / Q000382:microbiology; D052899:Pore Forming Cytotoxic Proteins / Q000276:immunology*; D016019:Survival Analysis; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D051216:Toll-Like Receptor 6 / Q000276:immunology*; D037521:Virulence Factors / Q000276:immunology*; D015010:Yersinia pestis / Q000276:immunology* / Q000472:pathogenicity
D000942:Antigens, Bacterial; D007155:Immunologic Factors; C043908:LcrV protein, Yersinia; D052899:Pore Forming Cytotoxic Proteins; D051216:Toll-Like Receptor 6; D037521:Virulence Factors; D016753:Interleukin-10