Yeast zymosan, a stimulus for TLR2 and dectin-1, induces regulatory antigen-presenting cells and immunological tolerance.
Emerging evidence suggests critical roles for APCs in suppressing immune responses. Here, we show that zymosan, a stimulus for TLR2 and dectin-1, regulates cytokine secretion in DCs and macrophages to induce immunological tolerance. First, zymosan induces DCs to secrete abundant IL-10 but little IL-6 and IL-12(p70). Induction of IL-10 is dependent on TLR2- and dectin-1-mediated activation of ERK MAPK via a mechanism independent of the activation protein 1 (AP-1) transcription factor c-Fos. Such DCs stimulate antigen-specific CD4+ T cells poorly due to IL-10 and the lack of IL-6. Second, zymosan induces F4-80+ macrophages in the splenic red pulp to secrete TGF-beta. Consistent with these effects on APCs, injection of zymosan plus OVA into mice results in OVA-specific T cells that secrete little or no Th1 or Th2 cytokines, but secrete robust levels of IL-10, and are unresponsive to challenge with OVA plus adjuvant. Finally, coinjection of zymosan with OVA plus LPS suppresses the response to OVA via a mechanism dependent on IL-10, TGF-beta, and lack of IL-6. Together, our data demonstrate that zymosan stimulates IL-10+ IL-12(p70)- IL-6low regulatory DCs and TGF-beta+ macrophages to induce immunological tolerance. These data suggest several targets for pharmacological modulation of immune responses in various clinical settings.
Dillon
Stephanie
S
Emory Vaccine Research Center and Department of Pathology, Emory University, Atlanta, Georgia 30329, USA.
Agrawal
Sudhanshu
S
Banerjee
Kaustuv
K
Letterio
John
J
Denning
Timothy L
TL
Oswald-Richter
Kyra
K
Kasprowicz
Deborah J
DJ
Kellar
Kathryn
K
Pare
Jeff
J
van Dyke
Thomas
T
Ziegler
Steven
S
Unutmaz
Derya
D
Pulendran
Bali
B
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D007108:Immune Tolerance; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D037181:Lectins, C-Type; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D013154:Spleen; D013997:Time Factors; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015003:Yeasts / Q000378:metabolism; D015054:Zymosan / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D000099181:Dectin-1
D016207:Cytokines; D048049:Extracellular Signal-Regulated MAP Kinases; D016753:Interleukin-10; D018664:Interleukin-12; D015850:Interleukin-6; D037181:Lectins, C-Type; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D016760:Proto-Oncogene Proteins c-fos; D051195:Toll-Like Receptor 2; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D015054:Zymosan; D000099181:Dectin-1