The first α helix of interleukin (IL)-2 folds as a homotetramer, acts as an agonist of the IL-2 receptor β chain, and induces lymphokine-activated killer cells

Abstract

Interleukin (IL)-2 interacts with two types of functional receptors (IL-2Rαβγ and IL-2Rβγ) 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 α helix A of IL-2) spontaneously folds into an α-helical homotetramer and stimulates the growth of T cell lines expressing human IL-2Rβ, 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-2Rβ. In agreement with its binding to IL-2Rβ, 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-2Rβ may bind to different Jaks depending on its oligomerization. At the cellular level, p1-30 induces lymphokine-activated killer (LAK) cells and preferentially activates CD8b(low) lymphocytes and natural killer cells, which constitutively express IL-2Rβ. A significant interferon γ 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.