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A Pivotal Role for CD40-Mediated IL-6 Production by Dendritic Cells during IL-17 Induction In Vivo¹

Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, Scotland, United Kingdom

The costimulatory requirements for Th17 development remain to be defined. In this study, we show that CD40-deficient animals immunized with the Gram-positive bacterium Propionibacterium acnes were specifically impaired in their ability to mount an IL-17 response, but not that of IFN-. The same cytokine imbalance resulted from in vivo priming with pathogen-pulsed, CD40-deficient dendritic cells (DC). Engagement of CD40 on P. acnes-conditioned DC stimulated the release of IL-12, IL-23, and IL-6, of which IL-6 alone proved essential for Th17 differentiation. Compared with wild-type DC, priming with those lacking expression of CD40 resulted in reduced disease severity during experimental autoimmune encephalomyelitis, coincident with reduced IL-17 production. Our data delineate sequential requirements for DC expression of CD40 and production of IL-6 during Th17 polarization in vitro and in vivo, and reveal distinct costimulatory requirements for Th1 vs Th17 generation.

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 funded by the Medical Research Council U.K. and the Wellcome Trust.

² G.P.W. and S.J.J. contributed equally to this study.

³ Current address: Trudeau Institute, Saranac Lake, NY 12983.

⁴ Address correspondence to Dr. Andrew MacDonald, Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh Scotland, U.K. E-mail address: andrew.macdonald{at}ed.ac.uk

⁵ Abbreviations used in this paper: DC, dendritic cell; WT, wild type; Pa, a heat-killed preparation of Propionibacterium acnes; St, a heat-killed preparation of Salmonella typhimurium; MOG, myelin oligodendrocyte glycoprotein; EAE, experimental autoimmune encephalomyelitis.

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