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J. Biol. Chem., Vol. 279, Issue 23, 24313-24322, June 4, 2004

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Identification of an Interleukin-15 Receptor-binding Site on Human Interleukin-15^*

Jérôme Bernard, Catherine Harb, Erwan Mortier¶, Agnès Quéméner, Rob H. Meloen||, Claudine Vermot-Desroches**, John Wijdeness**, Peter van Dijken||, Joachim Grötzinger, Jerry W. Slootstra||, Ariane Plet, and Yannick Jacques

From the Groupe de Recherche Cytokines et Récepteurs, Unité INSERM 601, Institut de Biologie, 9 Quai Moncousu, 44093 Nantes Cedex 01, France, ^||Pepscan Systems, Edelhertweg 15, 8219 PH Lelystad, The Netherlands, ^**Diaclone, 1 Bld A. Fleming, BP 1985, 25020 Besançon Cedex, France, and the Department of Biochemistry, Christian-Albrechts-Universität zu Kiel, Olshausenstrasse 40, D-24098, Kiel, Germany

To identify the epitopes in human interleukin-15 (IL-15) that are responsible for binding to the interleukin-15 receptor chain, antibody and receptor mapping by peptide scanning and site-directed mutagenesis was used. By using peptide scanning, we identified four regions in IL-15. The first region (⁸⁵CKECEELEEKN⁹⁵) is located in the C-D loop and is recognized by a set of non-inhibitory antibodies. The second region (¹⁰²SFVHIVQMFIN¹¹²) is located in helix D and is recognized by two antibodies that are inhibitory of IL-15 bio-activity but not of IL-15 binding to IL-15R. The two remaining regions react with a recombinant soluble form of the IL-15R; the first (⁴⁴LLELQVISL⁵², peptide 1) corresponds to a sequence located in the B-helix and the second (⁶⁴ENLII⁶⁸, peptide 2) to a sequence located in helix C. The latter is also contained in the epitope recognized by an antibody (monoclonal antibody B-E29) that prevents IL-15 binding to IL-15R. By site-directed mutagenesis, we confirmed that residues present in peptide 1 (Leu-45, Glu-46, Val-49, Ser-51, and Leu-52) and peptide 2 (Leu-66 and Ile-67) are involved in the binding of IL-15 to IL-15R. Furthermore, the results presented indicate that residues in the second peptide (Glu-64, Asn-65, and Ile-68) participate in IL-2R recruitment. This finding could have implications for the dynamics of receptor assembly. These results also indicate that the modes of interaction of IL-15 and IL-2 with their respective chains are not completely analogous. Finally, some of the IL-15 mutants generated in this study displayed agonist or antagonist properties and may be useful as therapeutic agents.

Received for publication, November 13, 2003 , and in revised form, March 2, 2004.

^* This work was supported in part by Grant P00/3/5692 from the Association pour la Recherche sur le Cancer, INSERM, and CNRS. 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.

Recipient of fellowships from the Ligue Nationale Contre le Cancer (Comité de Vendée) and from the ARC.

^¶ Recipient of a fellowship from the Ministère de la Recherche et des Nouvelles Technologies.

To whom correspondence should be addressed. Tel.: 33-2-40-08-47-23; Fax: 33-2-40-35-66-97; E-mail: yjacques{at}nantes.inserm.fr.

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