The immune response modifier and Toll-like receptor 7 agonist S-27609 selectively induces IL-12 and TNF-alpha production in CD11c+CD11b+CD8- dendritic cells.
IL-12 and TNF-alpha production by dendritic cells (DCs) is a critical step in the initiation of local inflammation and adaptive immune responses. We show in this study that a small molecule immune response modifier that is a Toll-like receptor 7 (TLR7) agonist induces IL-12 and TNF-alpha production from murine CD11c(+)CD11b(+)CD8(-) DCs, a subset not previously known for this activity. Stimulation of these DCs through TLR7 in vivo induces significant cytokine production even 12 h after initial stimulation, as well as migration of the DC into T cell zones of the lymphoid tissue. In contrast, stimulation through TLR4 and TLR9 induced IL-12 production predominantly from CD8(+) DCs, consistent with previously published data. All TLR stimuli induced the increase in surface expression of the activation markers B7-1, B7-2, and class II in both CD8(+) and CD8(-) DCs, demonstrating that CD8(+) DCs do respond to TLR7-mediated stimuli. To date this is the only known stimuli to induce preferential cytokine production from CD8(-) DCs. Given the efficacy of TLR7 agonists as antiviral agents, the data collectively indicate that stimulation of CD8(-) DCs through TLR7 most likely plays a role in the generation of antiviral immune responses.
Doxsee
Christie L
CL
Department of Pharmacology, 3 M Pharmaceuticals, St Paul, MN 55144, USA.
Riter
Tony R
TR
Reiter
Michael J
MJ
Gibson
Shelia J
SJ
Vasilakos
John P
JP
Kedl
Ross M
RM
D000634:Aminoquinolines / Q000008:administration & dosage*; D000818:Animals; D039481:CD11b Antigen / Q000096:biosynthesis*; D039521:CD11c Antigen / Q000096:biosynthesis*; D016827:CD8 Antigens / Q000096:biosynthesis; D002460:Cell Line; D002465:Cell Movement / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000819:agonists / Q000502:physiology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D007275:Injections, Intravenous; D018664:Interleukin-12 / Q000096:biosynthesis*; D008562:Membrane Glycoproteins / Q000819:agonists* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000819:agonists* / Q000502:physiology; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
C095471:4-amino-alpha,alpha,2-trimethyl-1H-imidazo(4,5-c)quinoline-1-ethanol; D000634:Aminoquinolines; D039481:CD11b Antigen; D039521:CD11c Antigen; D016827:CD8 Antigens; D016207:Cytokines; D004268:DNA-Binding Proteins; D007155:Immunologic Factors; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; C495371:TLR9 protein, human; C477038:Tlr7 protein, mouse; C495370:Tlr9 protein, mouse; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12