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The Cyclic AMP Response Element Modulator Suppresses CD86 Expression and APC Function¹

Martina Ahlmann^*,, Georg Varga^*, Karsten Sturm^*,, Ralph Lippe^*,, Konrad Benedyk^*,, Dorothee Viemann^*, Thomas Scholzen, Jan Ehrchen^*, Frank U. Müller^¶, Matthias Seidl^¶, Marek Matus^¶, George C. Tsokos^||, Johannes Roth^*, and Klaus Tenbrock^2,*,,#

^* Institute of Immunology, Department of Pediatrics, Interdisziplinäres Zentrum für Klinische Forschung Research Group 5, Institute of Cell Biology, ^¶ Institute of Pharmacology and Toxicology, University of Münster, Münster Germany; ^|| Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115; and ^# Department of Pediatrics, Rheinisch-Westfälische Technische Hochschule, Aachen University, Aachen, Germany

The cAMP response element modulator (CREM) is a widely expressed transcriptional repressor that is important for the termination of the T cell immune response and contributes to the abnormal T cell function in patients with systemic lupus erythematosus. We present evidence that APCs of Crem^–/– mice express increased amounts of the costimulatory molecule CD86 and induce enhanced Ag-dependent and Ag-independent T cell proliferation. Similarly, human APCs in which CREM was selectively suppressed expressed more CD86 on the surface membrane. CREM was found to bind to the CD86 promoter and suppressed its activity. Transfer of APCs from Crem^–/– mice into naive mice facilitated a significantly stronger contact dermatitis response compared with mice into which APCs from Crem^+/+ mice had been transferred. We conclude that CREM is an important negative regulator of costimulation and APC-dependent T cell function both in vitro and 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 is supported in part by a Public Health Service Grant R01 AI 49954, a Deutsche Forschungsgemeinschaft Grant TE 339/4-3, and an Interdisziplinäres Zentrum für Klinische Forschung Münster Grant FG5.

² Address correspondence and reprint requests to Dr. Klaus Tenbrock, Department of Pediatrics, Division of Pediatric Pulmonology, Allergology and Immunology, Klinikum der Rheinisch-Westfälische Technische Hochschule Aachen, Pauwelsstrasse 30, D-52074 Aachen, Germany. E-mail address: ktenbrock{at}ukaachen.de

³ Abbreviations used in this paper: CREM, cAMP response element modulator; SLE, systemic lupus erythematosus; DC, dendritic cell; ChIP, chromatin immunoprecipitation; BMDC, bone marrow-derived DC; HDAC, histone deacetylase; CRE, cAMP response element.