Crystal structure of the IL-15–IL-15Rα complex, a cytokine-receptor unit presented in trans

Abstract

Interleukin 15 (IL-15) and IL-2, which promote the survival of memory CD8(+) T cells and regulatory T cells, respectively, bind receptor complexes that share beta- and gamma-signaling subunits. Receptor specificity is provided by unique, nonsignaling alpha-subunits. Whereas IL-2 receptor-alpha (IL-2Ralpha) is expressed together in cis with the beta- and gamma-subunits on T cells and B cells, IL-15Ralpha is expressed in trans on antigen-presenting cells. Here we present a 1.85-A crystal structure of the human IL-15-IL-15Ralpha complex. The structure provides insight into the molecular basis of the specificity of cytokine recognition and emphasizes the importance of water in generating this very high-affinity complex. Despite very low IL-15-IL-2 sequence homology and distinct receptor architecture, the topologies of the IL-15-IL-15Ralpha and IL-2-IL-2Ralpha complexes are very similar. Our data raise the possibility that IL-2, like IL-15, might be capable of being presented in trans in the context of its unique receptor alpha-chain.

No Requirement of Trans Presentations of IL-15 for Human CD8 T Cell Proliferation

“…The functional difference between IL-15 and the IL-15-IL-15Ra complex on cells expressing Rb/g is probably attributable to the structural differences between free IL-15 and IL-15 bound to the IL-15Ra. We and others have resolved the structure of the IL-15-IL-15Ra complex (17,24), and we are currently analyzing the structure of free IL-15 to confirm this proposition.…”

“…Crystallographic analysis of the IL-15-IL-15Ra complex has provided no structural basis for the cis and trans presentation of IL-15 (17,24). In both the human and mouse structures, the importance of the Sushi domain of IL-15Ra in binding to IL-15 has been clearly shown, but there is no information concerning the stalk portion of the receptor.…”

Nanometer-scale organization of the alpha subunits of the receptors for IL2 and IL15 in human T lymphoma cells

“…For instance, the pathogen recognition receptor DC-SIGN also forms domains at the submicron scale on immature dendritic cells, but with a rather heterogeneous packing density (de Bakker et al, 2007). It has been postulated recently that, owing to its substantial glycosylation, the structure of IL2R␣ is relatively rigid, forming a notable entropic barrier preventing the formation of the quaternary receptor complex (Chirifu et al, 2007). We hypothesize that association with MHC glycoproteins might compensate for this entropic barrier.…”

Small-Molecule Inhibitors of IL-2/IL-2R: Lessons Learned and Applied

“…A similar cytokine:sushi domain interaction defines the recognition of IL-15 by IL-15-Ra, but the binding surface is physically and chemically very different (Chirifu et al 2007). The contact area is~30% smaller and is much more hydrophilic, with a pronounced acidic groove on IL-15 binding to a highly basic protrusion on IL-15Ra.…”