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Accessory Protein-Like Is Essential for IL-18-Mediated Signaling¹

Heidi Cheung^2,*, Nien-Jung Chen^2,*, Zhaodan Cao, Nobuyuki Ono^*, Pamela S. Ohashi^* and Wen-Chen Yeh^3,*

^* Advanced Medical Discovery Institute/Campbell Family Institute for Breast Cancer Research, University Health Network and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; and Amgen, South San Francisco, CA 94080

IL-18 is an essential cytokine for both innate and adaptive immunity. Signaling by IL-18 requires IL-18R, which binds specifically to the ligand and contains sequence homology to IL-1R and TLRs. It is well established that IL-1R signaling requires an accessory cell surface protein, AcP. Other accessory proteins also exist with roles in regulating TLR signaling, but some have inhibitory functions. An AcP-like molecule (AcPL) has been identified with the ability to cooperate with IL-18R in vitro; however, the physiological function of AcPL remains unknown. In this study, we demonstrate that IL-18 signals are abolished in AcPL-deficient mice and cells. Splenocytes from mutant mice fail to respond to IL-18-induced proliferation and IFN- production. In particular, Th1 cells lacking AcPL fail to produce IFN- in response to IL-18. AcPL-deficient neutrophils also fail to respond to IL-18-induced activation and cytokine production. Furthermore, AcPL is required for NK-mediated cytotoxicity induced by in vivo IL-18 stimulation. However, AcPL is dispensable for the activation or inhibition of IL-1R and the various TLR signals that we have examined. These results suggest that AcPL is a critical and specific cell surface receptor that is required for IL-18 signaling.

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