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J. Biol. Chem., Vol. 281, Issue 3, 1612-1619, January 20, 2006

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Soluble Interleukin-15 Receptor (IL-15R)-sushi as a Selective and Potent Agonist of IL-15 Action through IL-15R/

HYPERAGONIST IL-15·IL-15R FUSION PROTEINS^*

Erwan Mortier1, Agnès Quéméner, Patricia Vusio, Inken Lorenzen¶, Yvan Boublik||, Joachim Grötzinger¶, Ariane Plet, and Yannick Jacques2

From the INSERM, U601, Groupe de Recherche Cytokines et Récepteurs, Institut de Biologie, Nantes F-44093, France, the Université de Nantes, Unité de Formation et de Recherche Médecine, IFR26, Institut de Biologie, Nantes F-44093, France, the ^¶Christian-Albrechts-Universität zu Kiel, Kiel D-24098, Germany, and the ^||CNRS, FRE 2593, Centre de Recherches de Biochimie Macromoléculaire, Montpellier, F-34293 France

Interleukin-15 (IL-15) is crucial for the generation of multiple lymphocyte subsets (natural killer (NK), NK-T cells, and memory CD8 T cells), and transpresentation of IL-15 by monocytes and dendritic cells has been suggested to be the dominant activating process of these lymphocytes. We have previously shown that a natural soluble form of IL-15R chain corresponding to the entire extracellular domain of IL-15R behaves as a high affinity IL-15 antagonist. In sharp contrast with this finding, we demonstrate in this report that a recombinant, soluble sushi domain of IL-15R, which bears most of the binding affinity for IL-15, behaves as a potent IL-15 agonist by enhancing its binding and biological effects (proliferation and protection from apoptosis) through the IL-15R/ heterodimer, whereas it does not affect IL-15 binding and function of the tripartite IL-15R// membrane receptor. Our results suggest that, if naturally produced, such soluble sushi domains might be involved in the IL-15 transpresentation mechanism. Fusion proteins (RLI and ILR), in which IL-15 and IL-15R-sushi are attached by a flexible linker, are even more potent than the combination of IL-15 plus sIL-15R-sushi. After binding to IL-15R/, RLI is internalized and induces a biological response very similar to the IL-15 high affinity response. Such hyper-IL-15 fusion proteins appear to constitute potent adjuvants for the expansion of lymphocyte subsets.

Received for publication, August 5, 2005 , and in revised form, October 26, 2005.

^* This work was supported in part by INSERM, the CNRS, and the Association de la Recherche Contre le Cancer (Grant A03/1/3311). 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 Supported by a fellowship from the Ministère de la Recherche et des Nouvelles Technologies and by fellowships from the Association pour la Recherche sur le Cancer and the Ligue Nationale Contre le Cancer.

² To whom correspondence should be addressed: INSERM U601, Groupe de Recherche Cytokines et Récepteurs, Institut de Biologie, 9 Quai Moncousu, 44093 Nantes Cedex 01, France. 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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