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 vivo

Wei, Xiao-Qing ORCID: https://orcid.org/0000-0002-6274-8503, Orchardson, Michael, Gracie, J. Alastair, Leung, Bernard P., Gao, Bao-mei, Guan, Hui, Niedbala, Wanda, Paterson, GK, McInnes, Iain B, and Liew, Foo Yew 2001. 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 vivo. The Journal of Immunology 167 (1) , pp. 277-282.

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Abstract

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 a-chain and the common IL-2R b- and g-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-15Ra (sIL-15Ra) by deleting the cytoplasmic and transmembrane domains. To localize the functional domain of IL-15Ra, we have now constructed various truncated versions of sIL-15Ra. The shortest region retaining IL-15 binding activity is a 65-aa sequence spanning the Sushi domain of IL-15Ra. 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-15Ra completely abolished its IL-15 binding activity. This also abrogated the ability of sIL-15Ra to neutralize IL-15- induced proinflammatory cytokine production and anti-apoptotic response in vitro. Furthermore, the mutant sIL-15Ra 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-15Ra.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Dentistry
Subjects:	Q Science > QR Microbiology > QR180 Immunology
Publisher:	American Association of Immunologists
ISSN:	0022-1767
Last Modified:	21 Oct 2022 09:14
URI:	https://orca.cardiff.ac.uk/id/eprint/35681

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