title: The first alpha helix of interleukin (IL)-2 folds as a homotetramer, acts as an agonist of the IL-2 receptor beta chain, and induces lymphokine-activated killer cells.
abstract: Interleukin (IL)-2 interacts with two types of functional receptors (IL-2Ralphabetagamma and IL-2Rbetagamma) 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 alpha helix A of IL-2) spontaneously folds into an alpha-helical homotetramer and stimulates the growth of T cell lines expressing human IL-2Rbeta, 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-2Rbeta. In agreement with its binding to IL-2Rbeta, 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-2Rbeta 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-2Rbeta. A significant interferon gamma production is also detected after p1-30 stimulation. A mutant form of p1-30 (Asp20-->Lys), 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.
authors.affiliation: Unité d'Immunogénétique Cellulaire, Institut Pasteur, 75015 Paris, France.
authors.forename: R
authors.initials: R
authors.lastname: Eckenberg
authors.forename: T
authors.initials: T
authors.lastname: Rose
authors.forename: J L
authors.initials: JL
authors.lastname: Moreau
authors.forename: R
authors.initials: R
authors.lastname: Weil
authors.forename: F
authors.initials: F
authors.lastname: Gesbert
authors.forename: S
authors.initials: S
authors.lastname: Dubois
authors.forename: D
authors.initials: D
authors.lastname: Tello
authors.forename: M
authors.initials: M
authors.lastname: Bossus
authors.forename: H
authors.initials: H
authors.lastname: Gras
authors.forename: A
authors.initials: A
authors.lastname: Tartar
authors.forename: J
authors.initials: J
authors.lastname: Bertoglio
authors.forename: S
authors.initials: S
authors.lastname: Chouaïb
authors.forename: M
authors.initials: M
authors.lastname: Goldberg
authors.forename: Y
authors.initials: Y
authors.lastname: Jacques
authors.forename: P M
authors.initials: PM
authors.lastname: Alzari
authors.forename: J
authors.initials: J
authors.lastname: Thèze
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000032:analysis; D007376:Interleukin-2 / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D015979:Killer Cells, Lymphokine-Activated / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000187:drug effects; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D016131:Lymphocyte Subsets / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009000:Monocytes / Q000187:drug effects; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology; D017510:Protein Folding; D015375:Receptors, Interleukin-2 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D018909:src Homology Domains
chemical_list: D007376:Interleukin-2; D010446:Peptide Fragments; D015375:Receptors, Interleukin-2; D007371:Interferon-gamma; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)