A Toll-like receptor 2 ligand stimulates Th2 responses in vivo, via induction of extracellular signal-regulated kinase mitogen-activated protein kinase and c-Fos in dendritic cells.
The adaptive immune system can generate distinct classes of responses, but the mechanisms that determine this are poorly understood. In this study, we demonstrate that different Toll-like receptor (TLR) ligands induce distinct dendritic cell (DC) activation and immune responses in vivo. Thus, Escherichia coli LPS (TLR-4 stimulus), activates DCs to produce abundant IL-12(p70), but little IL-10, and stimulates Th1 and Tc1 responses. In contrast, Pam-3-cys (TLR-2 stimulus) elicits less IL-12(p70), but abundant IL-10, and favors Th2 and T cytotoxic 2 (Tc2) responses. These distinct responses likely occur via differences in extracellular signal-regulated kinase signaling in DCs. Thus, Pam-3-cys induces enhanced extracellular signal-regulated kinase signaling, compared with LPS, resulting in suppressed IL-12(p70) and enhanced IL-10 production, as well as enhanced induction of the transcription factor, c-Fos. Interestingly, DCs from c-fos(-/-) mice produce more IL-12(p70), but less IL-10, compared with control DCs. Therefore, different TLR ligands induce distinct cytokines and signaling in DCs, and differentially bias Th responses in vivo.
Dillon
Stephanie
S
Vaccine Research Center, Emory University, Atlanta, GA 30329, USA.
Agrawal
Anshu
A
Van Dyke
Thomas
T
Landreth
Gary
G
McCauley
Laurie
L
Koh
Amy
A
Maliszewski
Charles
C
Akira
Shizuo
S
Pulendran
Bali
B
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000502:physiology; D039481:CD11b Antigen / Q000378:metabolism; D039521:CD11c Antigen / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D004151:Dipeptides / Q000378:metabolism / Q000494:pharmacology; D004790:Enzyme Induction / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D004926:Escherichia coli / Q000276:immunology; D017781:Genes, Immediate-Early / Q000276:immunology; D016753:Interleukin-10 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008024:Ligands; D008070:Lipopolysaccharides / Q000378:metabolism / Q000494:pharmacology; D008074:Lipoproteins / Q000378:metabolism / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000276:immunology*; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D053594:Myeloid Differentiation Factor 88; D010047:Ovalbumin / Q000276:immunology; D010766:Phosphorylation; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis* / Q000502:physiology; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism*; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D039481:CD11b Antigen; D039521:CD11c Antigen; D004151:Dipeptides; D018984:Epitopes, T-Lymphocyte; D008024:Ligands; D008070:Lipopolysaccharides; D008074:Lipoproteins; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D021122:Protein Subunits; D016760:Proto-Oncogene Proteins c-fos; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D016753:Interleukin-10; D018664:Interleukin-12; D010047:Ovalbumin; C047210:2,3-bis-(palmitoyloxy)-2-propyl-N-palmitoyl-cysteinylserine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases