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IL-2Rß Agonist P1–30 Acts in Synergy with IL-2, IL-4, IL-9, and IL-15: Biological and Molecular Effects¹

Ralph Eckenberg^*, Jean-Louis Moreau^*, Oleg Melnyk and Jacques Thèze^2,*

^* Unité d’Immunogénétique Cellulaire, Institut Pasteur, Paris, France; and Institut de Biologie and Institut Pasteur, Lille, France

From the sequence of human IL-2 we have recently characterized a peptide (p1–30), which is the first IL-2 mimetic described. P1–30 covers the entire helix A of IL-2 and spontaneously folds into a helical homotetramer mimicking the quaternary structure of a hemopoietin. This neocytokine interacts with a previously undescribed dimeric form of the human IL-2 receptor ß-chain likely to form the p1–30 receptor (p1–30R). P1–30 acts as a specific IL-2Rß agonist, selectively inducing activation of CD8 and NK lymphocytes. From human PBMC we have also shown that p1–30 induces the activation of lymphokine-activated killer cells and the production of IFN-. Here we demonstrate the ability of p1–30 to act in synergy with IL-2, -4, -9, and -15. These synergistic effects were analyzed at the functional level by using TS1ß, a murine T cell line endogenously expressing the common cytokine gene and transfected with the human IL-2Rß gene. At the receptor level, we show that expression of human IL-2Rß is absolutely required to obtain synergistic effects, whereas IL-2R specifically impedes the synergistic effects obtained with IL-2. The results suggest that overexpression of IL-2R inhibits p1–30R formation in the presence of IL-2. Finally, concerning the molecular effects, although p1–30 alone induces the antiapoptotic molecule bcl-2, we show that it does not influence mRNA expression of c-myc, c-jun, and c-fos oncogenes. In contrast, p1–30 enhances IL-2-driven expression of these oncogenes. Our data suggest that p1–30R (IL-2Rß)₂ and intermediate affinity IL-2R (IL-2Rß), when simultaneously expressed at the cell surface, may induce complementary signal transduction pathways and act in synergy.

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