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

Zymosan induces IL-10 in human and murine DCs via a mechanism involving dectin-1.

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Zymosan induces IL-10 in human and murine DCs via a mechanism involving...
(A) Immature, monocyte-derived DCs were cultured for 24–48 hours with E. coli LPS (1 μg/ml) or zymosan (50 μg/ml), and flow cytometric analyses of the expression of the costimulatory molecules CD80 and CD86 and the maturation marker CD83 were performed. Filled histograms show isotype; open histograms represent marker. Data are representative of 10 experiments. (B) Secretion of cytokines in the culture supernatants was measured by ELISA. Data are representative of 18 experiments. (C) Murine, splenic CD11c+CD11b+CD8α–, and CD11c+CD11b–CD8α+ DC subsets were isolated by flow cytometry and cultured in vitro with E. coli LPS or zymosan for 24–48 hours in the presence of a CD40-L–expressing cell line. Cytokines were analyzed by ELISA. Data are representative of 10 experiments. (D) Immature, monocyte-derived DCs were cultured for 24–48 hours with laminarin (200 μg/ml) plus zymosan or with zymosan alone. IL-10 levels were measured after 24 hours by ELISA. Data are representative of 4 experiments. (E) CD11c+ murine splenic DCs were cultured with laminarin (200 μg/ml) plus zymosan and CD40-L–expressing fibroblasts. IL-10 levels were measured after 24 hours by ELISA. Data are representative of 7 experiments.