Characterization of the trans and cis presentation functions of IL-15 receptor alpha on tumor cells and T cells

IL-15 regulates many aspects of the development and function of immune cells, including CD8+ T and NK cells. IL-15 can be presented by IL-15 receptor alpha (IL15-RA) to bind with IL-2/IL-15 receptor beta (beta) and common gamma chains (gammac), which activate signaling pathways on NK and CD8+ T cells. Because IL-15RA as well as the beta/gammac complex are expressed on the surface of CD8+ T cells, it was originally proposed that IL-15 signals by binding with high affinity to a heterotrimeric IL-15Ralpha/beta/gammac complex on T cells. It was subsequently discovered that IL-15RA on other cells can bind and present IL-15 to NK and CD8+ cells in trans. Due to the later discovery of trans-presentation, much of what we know about IL-15 and its signaling pathways have been elucidated based on the original view that IL-15 acts as a soluble rather than trans-presented cytokine. Therefore, the functional significance of and signaling components involved in IL-15 signaling in cis versus in trans are still poorly characterized.;Herein, we study the function and signaling components of IL-15 presented by IL-15RA in trans and in cis. Using tumor cells expressing a construct linking IL-15 to IL-15RA (IL-15/IL-15RA) and tumor cells expressing a gammac binding mutant of the same construct, we demonstrate that trans-presentation of IL-15 by IL-15RA on tumor cells resulted in increased beta/gammac binding dependent signaling, activation, and in vivo tumor infiltration of CD8 T cells and NK cells. This ultimately resulted in NK1.1+ and CD8+ T cell dependent inhibition of tumor growth. We also demonstrate, using a novel method of CD8+ T cell transfection, that IL-15RA on CD8+ T cells can enhance IL-15 functions in cis. Transfection with IL-15RA RNA led to enhanced signaling, beta/gammac binding dependent viability, and proliferation in vivo of adoptively transferred naive CD8+ T cells. Furthermore, transfection or transduction with the IL-15/IL-15RA construct cell autonomously enhances the function of naive and tumor antigen specific CD8+ T cells. Together our data provide novel insights into signaling and the functional consequences of trans-presentation of IL-15 by IL-15RA on tumor cells and the cis-presentation of IL-15 by IL-15RA on T cells.