Enhancement of anti-viral function of human NK cells by soluble CD70 protein

Abstract

Natural killer (NK) cells are parts of innate immunity and capable of killing tumor cells and vi-rus-infected cells. Their cytolytic activity is regulated by signals from activating and inhibitory NK re-ceptors. In the present study, a human soluble receptor library was constructed, and NK cell-activating soluble proteins were screened from the library by evaluating IFN-γ production from NK cells. Conse-quently, CD70, PRNP, DKK1, PECAM1, and IL-10RA were identified as novel NK cell-activating soluble proteins. Among these NK cell-activating soluble proteins, the effect of soluble CD70 on NK cells was further investigated. CD27, the receptor for CD70, was preferentially expressed on $CD56^{bright}$ NK cells, and soluble CD70 protein bound to $CD27^+CD56^{bright}$ NK cells. While soluble CD70 protein enhanced IFN-γ secre-tion by $CD56^{bright}$ NK cells in the presence of IL-12, it augmented neither cytolytic activity nor prolif-eration of NK cells. Thus, it was investigated if soluble CD70 protein could be used to induce non-cytolytic antiviral activity of NK cells using an in vitro hepatitis C virus (HCV) infection system. Sol-uble CD70 protein stimulated NK cells to suppress HCV replication by enhancing NK cell IFN-γ se-cretion without killing infected cells. Taken together, CD27 engagement by a soluble CD70 protein enhances non-cytolytic antiviral activity of $CD56^{bright}$ NK cells by IFN-γ secretion. Thus, this soluble CD70 protein may be useful for the treatment of viral infections such as HCV infection.