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J. Biol. Chem., Vol. 281, Issue 50, 38535-38542, December 15, 2006

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Small Organic Compounds Enhance Antigen Loading of Class II Major Histocompatibility Complex Proteins by Targeting the Polymorphic P1 Pocket^*

Sabine Höpner¹, Katharina Dickhaut^**, Maria Hofstätter, Heiko Krämer, Dominik Rückerl, J. Arvid Söderhäll, Shashank Gupta², Viviana Marin-Esteban, Ronald Kühne³, Christian Freund^¶3, Günther Jung^||3, Kirsten Falk³⁴, and Olaf Rötzschke³⁵

From the Max-Delbrück-Center for Molecular Medicine (MDC), Robert-Rössle-Strasse 10, D-13125 Berlin, Germany, the Forschungsinstitut for Molecular Pharmacology (FMP), Robert-Rössle-Strasse 10, D-13125 Berlin, Germany, the ^¶Freie Universität Berlin, Thielallee 63, D-14195 Berlin, Germany, the ^||Eberhard-Karls University, Auf der Morgenstelle 18, D-72076 Tübingen, Germany, and the ^**Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany

Major histocompatibility complex (MHC) molecules are a key element of the cellular immune response. Encoded by the MHC they are a family of highly polymorphic peptide receptors presenting peptide antigens for the surveillance by T cells. We have shown that certain organic compounds can amplify immune responses by catalyzing the peptide loading of human class II MHC molecules HLA-DR. Here we show now that they achieve this by interacting with a defined binding site of the HLA-DR peptide receptor. Screening of a compound library revealed a set of adamantane derivatives that strongly accelerated the peptide loading rate. The effect was evident only for an allelic subset and strictly correlated with the presence of glycine at the dimorphic position 86 of the HLA-DR molecule. The residue forms the floor of the conserved pocket P1, located in the peptide binding site of MHC molecule. Apparently, transient occupation of this pocket by the organic compound stabilizes the peptide-receptive conformation permitting rapid antigen loading. This interaction appeared restricted to the larger Gly⁸⁶ pocket and allowed striking enhancements of T cell responses for antigens presented by these "adamantyl-susceptible" MHC molecules. As catalysts of antigen loading, compounds targeting P1 may be useful molecular tools to amplify the immune response. The observation, however, that the ligand repertoire can be affected through polymorphic sites form the outside may also imply that environmental factors could induce allergic or autoimmune reactions in an allele-selective manner.

Received for publication, July 6, 2006

^* 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.

This article was selected as a Paper of the week.

¹ Supported by a grant awarded by a Ph.D. stipend program of the Max-Delbrück-Center.

² Supported by the Marie-Curie Research Training Network "Drugs for Therapy" program.

³ These authors were all supported by the Federal Ministry of Education and Research-sponsored "MHCenhancer" network.

⁴ To whom correspondence may be addressed. Tel.: 49-30-9406-3664; Fax: 49-30-9406-2394; E-mail: falk{at}mdc-berlin.de. ⁵ To whom correspondence may be addressed. Tel.: 49-30-9406-3664; Fax: 49-30-9406-2394; E-mail: roetzsch{at}mdc-berlin.de.

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