Yeast zymosan, a stimulus for TLR2 and dectin-1, induces regulatory antigen-presenting cells and immunological tolerance
Stephanie Dillon, … , Derya Unutmaz, Bali Pulendran
Stephanie Dillon, … , Derya Unutmaz, Bali Pulendran
Published April 3, 2006
Citation Information: J Clin Invest. 2006;116(4):916-928. https://doi.org/10.1172/JCI27203.
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Research Article Immunology

Yeast zymosan, a stimulus for TLR2 and dectin-1, induces regulatory antigen-presenting cells and immunological tolerance

Abstract

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-β. 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-β, and lack of IL-6. Together, our data demonstrate that zymosan stimulates IL-10+IL-12(p70)–IL-6low regulatory DCs and TGF-β+ macrophages to induce immunological tolerance. These data suggest several targets for pharmacological modulation of immune responses in various clinical settings.

Authors

Stephanie Dillon, Sudhanshu Agrawal, Kaustuv Banerjee, John Letterio, Timothy L. Denning, Kyra Oswald-Richter, Deborah J. Kasprowicz, Kathryn Kellar, Jeff Pare, Thomas van Dyke, Steven Ziegler, Derya Unutmaz, Bali Pulendran

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Figure 6

Zymosan is not a potent inducer of costimulatory molecules on splenic DCs or proinflammatory cytokines in vivo.

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Zymosan is not a potent inducer of costimulatory molecules on splenic DC...
To investigate the effect of zymosan in vivo, C57BL/6 mice were injected with PBS containing either 10 μg E. coli LPS or 25 μg or 100 μg zymosan. (A) Either 4 or 10 hours later, spleens were removed and a small portion digested with collagenase type 4 (1 mg/ml; Worthington Biochemical Corp.) in complete DMEM plus 2% FBS for 30 minutes at 37°C. The red blood cells were lysed and the cell suspension washed twice prior to analysis of cell surface–expressed activation markers by flow cytometry. (B) C57BL/6 mice were injected with PBS containing either 10 μg E. coli LPS or 25 μg zymosan. Blood samples were removed at 1, 4, and 10 hours and serum cytokines analyzed by ELISA.