Crystal structure of the interleukin-15•interleukin-15 receptor α complex -: Insights into trans and cis presentation

Interleukin (IL)-15 is a pleiotropic cytokine that plays a pivotal role in both innate and adaptive immunity. IL-15 is unique among cytokines due to its participation in a trans signaling mechanism in which IL-15 receptor alpha(IL-15R alpha) from one subset of cells presents IL-15 to neighboring IL-2R beta/gamma(c)-expressing cells. Here we present the crystal structure of IL-15 in complex with the sushi domain of IL-15R alpha. The structure reveals that the alpha receptor-binding epitope of IL-15 adopts a unique conformation, which, together with amino acid substitutions, permits specific interactions with IL-15R alpha that account for the exceptionally high affinity of the IL-15 center dot IL-15R alpha complex. Interestingly, analysis of the topology of IL-15 and IL-15R alpha at the IL-15 center dot IL-15R alpha interface suggests that IL-15 should be capable of participating in a cis signaling mechanism similar to that of the related cytokine IL-2. Indeed, we present biochemical data demonstrating that IL-15 is capable of efficiently signaling in cis through IL-15R alpha and IL-2R beta/gamma(c) expressed on the surface of a single cell. Based on our data we propose that cis presentation of IL-15 may be important in certain biological contexts and that flexibility of IL-15R alpha permits IL-15 and its three receptor components to be assembled identically at the ligand-receptor interface whether IL-15 is presented in cis or trans. Finally, we have gained insights into IL-15 center dot IL-15R alpha center dot IL-2R beta center dot gamma(c) quaternary complex assembly through the use of molecular modeling.