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.
Emory Vaccine Research Center and Department of Pathology, Emory University, Atlanta, Georgia 30329, USA.
Stephanie
S
Dillon
Sudhanshu
S
Agrawal
Kaustuv
K
Banerjee
John
J
Letterio
Timothy L
TL
Denning
Kyra
K
Oswald-Richter
Deborah J
DJ
Kasprowicz
Kathryn
K
Kellar
Jeff
J
Pare
Thomas
T
van Dyke
Steven
S
Ziegler
Derya
D
Unutmaz
Bali
B
Pulendran
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