TLR5 ligation by flagellin converts tolerogenic dendritic cells into activating antigen-presenting cells that preferentially induce T-helper 1 responses.
Dendritic cells (DCs) differentiated in the presence of IL-10 preferentially induce regulatory T-cells and tolerance. Whether the tolerogenic properties displayed by these DCs (Tol-DCs) can be overcome has not been fully explored. Here we show for the first time that Tol-DCs express higher levels of TLR5 mRNA, but not TLR4 or TLR9 mRNA relative to DCs differentiated with GM-CSF and IL-4 (BM-DCs). In response to flagellin, a natural TLR-5 ligand, Tol-DCs produced IL-12 but not IL-10. Unlike Tol-DCs stimulated with LPS, which produce high levels of IL-10 and fail to generate a cognate inflammatory response in CD4(+) T-cells, flagellin-stimulated Tol-DCs promoted the differentiation of CD4(+) T cells with a T-helper 1 phenotype. The divergent T-cell outcomes induced by Tol-DCs in response to different TLR-ligands highlights not only their plasticity, but also points to TLR5 ligation as a potential strategy to overcome tolerance in environments that are otherwise conducive to immune unresponsiveness.
Vicente-Suarez
Ildelfonso
I
Division of Immunology and Division of Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, United States.
Brayer
Jason
J
Villagra
Alejandro
A
Cheng
Fengdong
F
Sotomayor
Eduardo M
EM
D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects; D001854:Bone Marrow Cells / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D005408:Flagellin / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism*; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism*; D015847:Interleukin-4 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051198:Toll-Like Receptor 5 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
D011948:Receptors, Antigen, T-Cell; D051198:Toll-Like Receptor 5; D005408:Flagellin; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor