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.
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.
Mortier
Erwan
E
INSERM, U601, Groupe de Recherche Cytokines et Récepteurs, Institut de Biologie, Nantes F-44093, France.
Quéméner
Agnès
A
Vusio
Patricia
P
Lorenzen
Inken
I
Boublik
Yvan
Y
Grötzinger
Joachim
J
Plet
Ariane
A
Jacques
Yannick
Y
D000818:Animals; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D019281:Dimerization; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit; D019409:Interleukin-15 / Q000737:chemistry / Q000494:pharmacology*; D053646:Interleukin-2 Receptor beta Subunit; D007700:Kinetics; D004915:Leukemia, Erythroblastic, Acute; D008958:Models, Molecular; D011485:Protein Binding; D017433:Protein Structure, Secondary; D018123:Receptors, Interleukin / Q000502:physiology*; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2 / Q000819:agonists* / Q000737:chemistry / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D014162:Transfection
C568159:IL-15Ralpha-sushi domain-linker-IL-15 fusion protein; C508024:IL15RA protein, human; C508020:IL2RB protein, human; C507941:IL2RG protein, human; D053631:Interleukin Receptor Common gamma Subunit; D019409:Interleukin-15; D053646:Interleukin-2 Receptor beta Subunit; D018123:Receptors, Interleukin; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins