title: Mechanistic and structural insight into the functional dichotomy between IL-2 and IL-15.
abstract: Interleukin 15 (IL-15) and IL-2 have distinct immunological functions even though both signal through the receptor subunit IL-2Rβ and the common γ-chain (γ(c)). Here we found that in the structure of the IL-15-IL-15Rα-IL-2Rβ-γ(c) quaternary complex, IL-15 binds to IL-2Rβ and γ(c) in a heterodimer nearly indistinguishable from that of the IL-2-IL-2Rα-IL-2Rβ-γ(c) complex, despite their different receptor-binding chemistries. IL-15Rα substantially increased the affinity of IL-15 for IL-2Rβ, and this allostery was required for IL-15 trans signaling. Consistent with their identical IL-2Rβ-γ(c) dimer geometries, IL-2 and IL-15 showed similar signaling properties in lymphocytes, with any differences resulting from disparate receptor affinities. Thus, IL-15 and IL-2 induced similar signals, and the cytokine specificity of IL-2Rα versus IL-15Rα determined cellular responsiveness. Our results provide new insights for the development of specific immunotherapeutics based on IL-15 or IL-2.
authors.affiliation: Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Ring
authors.forename: Jian-Xin
authors.initials: JX
authors.lastname: Lin
authors.forename: Dan
authors.initials: D
authors.lastname: Feng
authors.forename: Suman
authors.initials: S
authors.lastname: Mitra
authors.forename: Mathias
authors.initials: M
authors.lastname: Rickert
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Bowman
authors.forename: Vijay S
authors.initials: VS
authors.lastname: Pande
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.forename: Ignacio
authors.initials: I
authors.lastname: Moraga
authors.forename: Rosanne
authors.initials: R
authors.lastname: Spolski
authors.forename: Engin
authors.initials: E
authors.lastname: Ozkan
authors.forename: Warren J
authors.initials: WJ
authors.lastname: Leonard
authors.forename: K Christopher
authors.initials: KC
authors.lastname: Garcia
mesh_terms: D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D006801:Humans; D019409:Interleukin-15 / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D007376:Interleukin-2 / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D053646:Interleukin-2 Receptor beta Subunit / Q000378:metabolism; D008024:Ligands; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D015398:Signal Transduction
chemical_list: D019409:Interleukin-15; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D053646:Interleukin-2 Receptor beta Subunit; D008024:Ligands