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

Citation
R. Eckenberg et al., 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, J EXP MED, 191(3), 2000, pp. 529-539
Citations number
39
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Medical Research General Topics
Journal title
JOURNAL OF EXPERIMENTAL MEDICINE
ISSN journal
0022-1007 → ACNP
Volume
191
Issue
3
Year of publication
2000
Pages
529 - 539
Database
ISI
SICI code
0022-1007(20000207)191:3<529:TFAHOI>2.0.ZU;2-G
Abstract
Interleukin (IL)-2 interacts with two types of functional receptors (IL-2R alpha beta gamma and IL-2R beta gamma) and acts on a broad range of target cells involved in inflammatory reactions and immune responses. For the firs t time, we show that a chemically synthesized fragment of the IL-2 sequence can fold into a molecule mimicking the quaternary structure of a hemopoiet in. Indeed, peptide p1-30 (containing amino acids 1-30, coveting the entire alpha helix A of IL-2) spontaneously folds into an alpha-helical homotetra mer and stimulates the growth of T cell lines expressing human IL-2R beta, whereas shorter versions of the peptide lack helical structure and are inac tive. We also demonstrate that this neocytokine interacts with a previously undescribed dimeric form of IL-2R beta. In agreement with its binding to I L-2R beta, p1-30 activates Shc and p56(lck) but unlike IL-2, fails to activ ate Janus kinase (Jak)1, Jak3, and signal transducer and activator of trans cription 5 (STAT5). Unexpectedly, we also show that p1-30 activates Tyk2, t hus suggesting that IL-2R beta 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 na tural killer cells, which constitutively express IL-2R beta. A significant interferon gamma production is also detected after p1-30 stimulation. A mut ant form of p1-30 (Asp20-->Lys), which is likely unable to induce vascular leak syndrome, remains capable of generating LAK cells, like the original p 1-30 peptide. Altogether, our data suggest that p1-30 has therapeutic poten tial.