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

• Type of Material: Article
• Authors: Stephanie Dillon, Emory University; Sudhanshu Agrawal, Emory University; Kaustuv Banerjee, Emory University; John Letterio, National Cancer Institute; Timothy Denning, Emory University; Kyra Oswald-Richter, Vanderbilt University Medical School; Deborah J. Kasprowicz, Benaroya Research Institute; Kathryn Kellar, Emory University; Jeff Pare, Emory University; Thomas van Dyke, Boston University School of Medicine; Steven Ziegler, Vanderbilt University Medical School; Derya Unutmaz, Vanderbilt University Medical School; Bali Pulendran, Emory University
• Language: English
• Date: 2006-04-03
• Publisher: American Society for Clinical Investigation
• Publication Version: Final Published Version
• Copyright Statement: © 2006, American Society for Clinical Investigation
• Final Published Version (URL): http://www.jci.org/articles/view/27203
• Title of Journal or Parent Work: Journal of Clinical Investigation
• Volume: 116
• Issue: 4
• Start Page: 916
• End Page: 928
• Grant/Funding Information: This work was supported by NIH grants AI0564499, AI048638, AI05726601, DK057665, AI057157, and AI05726601.
• Research Categories: Health Sciences, Immunology; Health Sciences, Pathology; Biology, Microbiology

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.