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.
View: Text | PDF
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

×

Figure 8

Zymosan induces antigen-specific T cell tolerance in vivo and suppresses the OVA-specific response when coinjected with OVA plus LPS.

Options: View larger image (or click on image) Download as PowerPoint
Zymosan induces antigen-specific T cell tolerance in vivo and suppresses...
(A) B6.PL mice reconstituted with OT-II TCR transgenic T cells were injected i.p. with class II–restricted OVA peptide, OVA323–339 (50 μg) plus LPS (25 μg), OVA323–339 (50 μg) plus zymosan (various doses), or OVA323–339 alone (50 μg). Four days later, spleens were removed and clonal expansion of OVA323–339–specific T cells (A) and numbers of OVA323–329-specific CD4+ T cells per spleen (B) were determined by flow cytometry. (C–E) Spleens were isolated 4 days after immunization, and unfractionated spleen cells labeled with CFSE and restimulated in vitro with OVA323–339 for 72 hours. Proliferation as measured by thymidine uptake (C) or CFSE labeling (D) and cytokine production by ELISA (E) were determined. Zymosan induced T cells that produced only high levels of IL-10 (box). Data are representative of 5 independent experiments. (F and G) Mice immunized as above with OVA323–339 plus LPS or OVA323–339 plus zymosan were rechallenged 10 days later with OVA323–339 in IFA. Four days after challenge, clonal expansion and cytokine production upon in vitro restimulation were evaluated. Data are representative of 4 independent experiments. (H and I) B6.PL mice reconstituted with OT-II TCR transgenic T cells were injected with OVA323–339 (50 μg) plus LPS (25 μg), OVA323–339 (50 μg) plus zymosan (100 μg), OVA323–339 (50 μg) plus LPS (25 μg) plus zymosan (100 μg), or OVA323–339 alone (50 μg). Four days later, spleens were removed and unfractionated splenocytes were restimulated with OVA323–339 and (H) CFSE and (I) proliferation of OVA323–339–specific T cells determined.