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Absence of IFN-β Impairs Antigen Presentation Capacity of Splenic Dendritic Cells via Down-Regulation of Heat Shock Protein 70¹

Natalia Zitara^2,*, Marcin yszkiewicz^3,*, Nelson Gekara^4,*, Jacek Puchaka, Vitor A. P. Martins Dos Santos, Clayton R. Hunt, Tej K. Pandita, Stefan Lienenklaus^* and Siegfried Weiss^*

^* Department of Molecular Biotechnology, Molecular Immunology Group, and Department of Molecular Biotechnology, Synthetic and Systems Biology Group, Helmholtz Centre for Infection Research, HZI, Braunschweig, Germany; and Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63108

Type I IFNs play a key role in linking the innate and adaptive arms of the immune system. Although produced rapidly in response to pathogens, IFNs are also produced at low levels in the absence of infection. In the present study, we demonstrate that constitutively produced IFNs are necessary in vivo to maintain dendritic cells in an "Ag presentation-competent" state. Conventional dendritic cells (cDCs) isolated from spleens of IFN-β or IFNAR-deficient mice exhibit a highly impaired ability to present Ag and activate naive T cells. Microarray analysis of mRNA isolated from IFN-β^–/– and IFNAR^–/– cDCs revealed diminished expression of two genes that encoded members of the heat shock protein 70 (Hsp70) family. Consistent with this observation, pharmacological inhibition of Hsp70 in cDCs from wild-type mice impaired their T cell stimulatory capacity. Similarly, the Ag presentation ability of splenic cDCs isolated from Hsp70.1/3^–/– mice was also severely impaired in comparison to wild-type cDCs. Thus, constitutive IFN-β expression regulates Hsp70 levels to help maintain dendritic cells in a competent state for efficient priming of effector T cells 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 in part by the Kultusministerium of Niedersachsen via the Lichtenberg PhD program, the German Research Council (Deutsche Forschungsgemeinschaft), the Marie Curie Action Miditrain MEST-CT-2004-504990, the Helmholtz Gemeinschaft via Helmholtz International Research School for Infection Biology, the Deutsche Krebshilfe, and the National Institutes of Health (CA10445 and CA123232).

² Address correspondence and reprint requests to Natalia Zietara, Molecular Immunology Group, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany. E-mail address: naz06{at}helmholtz-hzi.de

³ Current address: Institute for Immunology, Hannover Medical School, Hannover, Germany.

⁴ Current address: Institute for Genetics, Department of Mouse Genetics and Inflammation, University of Cologne, Cologne, Germany.

⁵ Abbreviations used in this paper: DC, dendritic cell; cDC, conventional DC; Hsp70, heat shock protein 70; poly(I:C), polyinosinic:polycytidylic acid; DSG, 15-deoxyspergualin; MHC I/II, MHC class I/class II; WT, wild type; qRT-PCR, quantitative RT-PCR.

⁶ The online version of this article contains supplemental material.