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Danger Signaling through the Inflammasome Acts as a Master Switch between Tolerance and Sensitization¹

Hideki Watanabe^2,*, Samuel Gehrke^*, Emmanuel Contassot^*,, Stéphanie Roques^*, Jürg Tschopp, Peter S. Friedmann, Lars E. French and Olivier Gaide^3,*

^* Departments of Dermatology and Pathology/Immunology, Geneva University Hospitals and University of Geneva, Geneva; Department of Biochemistry, University of Lausanne, Epalinges; Deptartment of Dermatology, Zürich University Hospital, Zürich, Switzerland; and Dermatopharmacology Unit, Medical School, Southampton General Hospital, Southampton, United Kingdom

Efficient priming of adaptive immunity depends on danger signals provided by innate immune pathways. As an example, inflammasome-mediated activation of caspase-1 and IL-1β is crucial for the development of reactive T cells targeting sensitizers like dinitrofluorobenzene (DNFB). Surprisingly, DNFB and dinitrothiocyanobenzene provide cross-reactive Ags yet drive opposing, sensitizing vs tolerizing, T cell responses. In this study, we show that, in mice, inflammasome-signaling levels can be modulated to turn dinitrothiocyanobenzene into a sensitizer and DNFB into a tolerizer, and that it correlates with the IL-6 and IL-12 secretion levels, affecting Th1, Th17, and regulatory T cell development. Hence, our data provide the first evidence that the inflammasome can define the type of adaptive immune response elicited by an Ag, and hint at new strategies to modulate T cell responses in vivo.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Swiss National Science Foundation. H.W. was supported by Mahuro Co. Ltd., Japan.

² Current address: Maruho Co., Ltd. Kyoto R&D Center, 93, Awata-cho, Chudoji; Shimogyo-ku, Kyoto, 600-8815, Japan.

³ Address correspondence and reprint requests to Dr. Olivier Gaide, Department of Dermatology and Pathology/Immunology, Geneva University Hospitals and University of Geneva, Michel-Servet 1, CH-1211 Geneva, Switzerland. E-mail address: olivier.gaide{at}medecine.unige.ch

⁴ Abbreviations used in this paper: NLR, NOD-like receptor; CHS, contact hypersensitivity; DNFB, dinitrofluorobenzene; ASC, Apoptosis-associated speck-like protein containing a CARD domain; DNCB, dinitrochlorobenzene; TNCB, trinitrochlorobenzene; IL-1RA, IL-1R antagonist; AOO, acetone olive oil; DNTB, dinitrothiocyanobenzene; Treg, regulatory T cell.