Soluble interleukin-15 receptor alpha (IL-15R alpha)-sushi as a selective and potent agonist of IL-15 action through IL-15R beta/gamma. Hyperagonist IL-15 x IL-15R alpha fusion proteins

J Biol Chem. 2006 Jan 20;281(3):1612-9. doi: 10.1074/jbc.M508624200. Epub 2005 Nov 11.


Interleukin-15 (IL-15) is crucial for the generation of multiple lymphocyte subsets (natural killer (NK), NK-T cells, and memory CD8 T cells), and transpresentation of IL-15 by monocytes and dendritic cells has been suggested to be the dominant activating process of these lymphocytes. We have previously shown that a natural soluble form of IL-15R alpha chain corresponding to the entire extracellular domain of IL-15R alpha behaves as a high affinity IL-15 antagonist. In sharp contrast with this finding, we demonstrate in this report that a recombinant, soluble sushi domain of IL-15R alpha, which bears most of the binding affinity for IL-15, behaves as a potent IL-15 agonist by enhancing its binding and biological effects (proliferation and protection from apoptosis) through the IL-15R beta/gamma heterodimer, whereas it does not affect IL-15 binding and function of the tripartite IL-15R alpha/beta/gamma membrane receptor. Our results suggest that, if naturally produced, such soluble sushi domains might be involved in the IL-15 transpresentation mechanism. Fusion proteins (RLI and ILR), in which IL-15 and IL-15R alpha-sushi are attached by a flexible linker, are even more potent than the combination of IL-15 plus sIL-15R alpha-sushi. After binding to IL-15R beta/gamma, RLI is internalized and induces a biological response very similar to the IL-15 high affinity response. Such hyper-IL-15 fusion proteins appear to constitute potent adjuvants for the expansion of lymphocyte subsets.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • Cell Line, Tumor
  • Cricetinae
  • Dimerization
  • Humans
  • Interleukin Receptor Common gamma Subunit
  • Interleukin-15 / chemistry
  • Interleukin-15 / pharmacology*
  • Interleukin-2 Receptor beta Subunit
  • Kinetics
  • Leukemia, Erythroblastic, Acute
  • Models, Molecular
  • Protein Binding
  • Protein Structure, Secondary
  • Receptors, Interleukin / physiology*
  • Receptors, Interleukin-15
  • Receptors, Interleukin-2 / agonists*
  • Receptors, Interleukin-2 / chemistry
  • Receptors, Interleukin-2 / physiology*
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / metabolism
  • Recombinant Fusion Proteins / pharmacology*
  • Transfection


  • IL-15Ralpha-sushi domain-linker-IL-15 fusion protein
  • IL15RA protein, human
  • IL2RB protein, human
  • IL2RG protein, human
  • Interleukin Receptor Common gamma Subunit
  • Interleukin-15
  • Interleukin-2 Receptor beta Subunit
  • Receptors, Interleukin
  • Receptors, Interleukin-15
  • Receptors, Interleukin-2
  • Recombinant Fusion Proteins