Original Article

The First Helix of Interleukin (IL)-2 Folds as a Homotetramer, Acts as an Agonist of the IL-2 Receptor ß Chain, and Induces Lymphokine-activated Killer Cells

Correspondence to: Jacques Thèze, Unité d'Immunogénétique Cellulaire, Département d'Immunologie, Institut Pasteur, 25 & 28 rue du Dr. Roux, 75724 Paris cedex 15, France. Tel:33-1-45-68-86-28/86-00 Fax:33-1-45-68-88-38 E-mail:jtheze{at}pasteur.fr.

Interleukin (IL)-2 interacts with two types of functional receptors (IL-2Rß and IL-2Rß) and acts on a broad range of target cells involved in inflammatory reactions and immune responses. For the first time, we show that a chemically synthesized fragment of the IL-2 sequence can fold into a molecule mimicking the quaternary structure of a hemopoietin. Indeed, peptide p1–30 (containing amino acids 1–30, covering the entire helix A of IL-2) spontaneously folds into an -helical homotetramer and stimulates the growth of T cell lines expressing human IL-2Rß, whereas shorter versions of the peptide lack helical structure and are inactive. We also demonstrate that this neocytokine interacts with a previously undescribed dimeric form of IL-2Rß. In agreement with its binding to IL-2Rß, p1–30 activates Shc and p56^lck but unlike IL-2, fails to activate Janus kinase (Jak)1, Jak3, and signal transducer and activator of transcription 5 (STAT5). Unexpectedly, we also show that p1–30 activates Tyk2, thus suggesting that IL-2Rß may bind to different Jaks depending on its oligomerization. At the cellular level, p1–30 induces lymphokine-activated killer (LAK) cells and preferentially activates CD8^low lymphocytes and natural killer cells, which constitutively express IL-2Rß. A significant interferon production is also detected after p1–30 stimulation. A mutant form of p1–30 (Asp20Lys), which is likely unable to induce vascular leak syndrome, remains capable of generating LAK cells, like the original p1–30 peptide. Altogether, our data suggest that p1–30 has therapeutic potential.

Key Words: interleukin 2 mimetic, synthetic hemopoietin, dimeric interleukin 2 receptor, ß chain, signal transduction, natural killer cells

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