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The Journal of Immunology, 2001, 167: 277-282.
Copyright © 2001 by The American Association of Immunologists

The Sushi Domain of Soluble IL-15 Receptor {alpha} Is Essential for Binding IL-15 and Inhibiting Inflammatory and Allogenic Responses In Vitro and In Vivo1

Xiao-qing Wei2,*, Michael Orchardson*, J. Alastair Gracie{dagger}, Bernard P. Leung*, Bao-mei Gao*, Hui Guan*, Wanda Niedbala*, Gavin K. Paterson*, Iain B. McInnes{dagger} and Foo Y. Liew2,*

* Department of Immunology and Bacteriology and {dagger} Center of Rheumatic Disease, University of Glasgow, Glasgow, United Kingdom

IL-15 is a pleiotropic cytokine that plays important roles in both innate and adaptive immunity. It is associated with a range of immunopathology, including rheumatoid arthritis and allograft rejection. IL-15 functions through the trimeric IL-15R complex, which consists of a high affinity binding {alpha}-chain and the common IL-2R {beta}- and {gamma}-chains. Characterization of IL-15/IL-15R interactions may facilitate the development of improved IL-15 antagonists for therapeutic interventions. We previously constructed soluble murine IL-15R{alpha} (sIL-15R{alpha}) by deleting the cytoplasmic and transmembrane domains. To localize the functional domain of IL-15R{alpha}, we have now constructed various truncated versions of sIL-15R{alpha}. The shortest region retaining IL-15 binding activity is a 65-aa sequence spanning the Sushi domain of IL-15R{alpha}. Sushi domains, common motifs in protein-protein interactions, contain four cysteines forming two disulfide bonds in a 1-3 and 2-4 pattern. Amino acid substitution of the first or fourth cysteine in sIL-15R{alpha} completely abolished its IL-15 binding activity. This also abrogated the ability of sIL-15R{alpha} to neutralize IL-15-induced proinflammatory cytokine production and anti-apoptotic response in vitro. Furthermore, the mutant sIL-15R{alpha} lost its ability to inhibit carrageenan-induced local inflammation and allogenic cell-induced T cell proliferation and cytokine production in vivo. Thus, the Sushi domain is critical for the functional activity of sIL-15R{alpha}.




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