Interleukin 15 is a pleiotropic cytokine of the four α helix bundle family. Binding to a heterotrimeric receptor complex, which consists of a unique, high affinity IL‑15Rα‑chain and IL-2/IL-15Rβ and IL‑2Rγ chains, IL‑15 activates signaling pathways leading to activation and proliferation of T and B cells, as well as natural killer cells. At the same time, IL‑15 protects effector cells from T regulatory cells and does not induce immune tolerance. The significant regulatory action of IL‑15 on the immune system provides new opportunities for development of anti‑cancer therapies. As documented in many experiments using different tumor models, IL‑15 enhances antitumor effects. To improve the efficiency of IL‑15, several strategies, including combination with other anti‑cancer therapies such as chemotherapy, additional use of antibodies (anti‑PD‑L1, anti‑CTLA‑4, anti‑CD40), or other cytokines, have been evaluated. Increased anti‑tumor activity can also be obtained by using IL‑15 agonists. However, acting as a growth factor for immune cells but also for tumor cells, IL‑15 may promote their proliferation, survival and dissemination. Of significance seems the role of IL‑15 in the pathogenesis of hematological malignancies, which is due to the involvement in the proliferation and differentiation of NK, T and B cells. Currently, several experimental strategies are available to block biological activity of IL‑15. Among compounds inhibiting the activity of IL‑15 are not only monoclonal antibodies interacting directly with the cytokine or with IL‑15R subunits, but also mutant forms of IL‑15 and protein constructs.

2012-01-01·Journal of peptide science : an official publication of the European Peptide Society4区 · 生物学

Enhancement of the inhibitory effect of an IL‐15 antagonist peptide by alanine scanning

4区 · 生物学

Article

作者: Chico, Araceli ; Aguero, Celia Aurora Arrieta ; Pérez, Haydee Gerónimo ; Ojeda, Miriam Ojeda ; Álvarez, Yunier Rodríguez ; Acosta, Osvaldo Reyes ; Estévez, Miguel ; Nieto, Gerardo Guillen ; Savio, Alicia Santos ; Pérez, Hilda Garay

IL‐15 is a proinflammatory cytokine that acts early in the inflammatory response and has been associated with several autoimmune diseases including rheumatoid arthritis, where it had been proposed as a therapeutic target. We recently reported an IL‐15 antagonist peptide corresponding to sequence 36–45 of IL‐15 (KVTAMKCFLL) named P8, which specifically binds to IL‐15Rα and inhibits IL‐15 biological activity with a half maximal inhibitory concentration (IC50) of 130 µ m in CTLL‐2 proliferation assay. In order to improve binding of peptide P8 to the receptor IL‐15Rα, we used an Ala scan strategy to study contribution of each individual amino acid to the peptide's antagonist effect. Here, we found that Phe and Cys are important for peptide binding to IL‐15Rα. We also investigated other single site mutations and replaced the second Lys in the sequence by the polar non‐charged amino acid threonine. The resulting peptide [K6T]P8 exhibited a higher activity than P8 with an IC50 of 24 µm. We also found that this peptide was more active than peptide P8 in the inhibition of TNFα secretion by synovial cells from rheumatoid arthritis patients. The peptide [K6T]P8 described in this work is a new type of IL‐15 antagonist and constitutes a potential therapeutic agent for rheumatoid arthritis. Copyright © 2011 European Peptide Society and John Wiley & Sons, Ltd.

2009-11-01·Immunology and cell biology3区 · 医学

NK cells enhance the induction of CTL responses by IL‐15 monocyte‐derived dendritic cells

3区 · 医学

Article

作者: Wilkinson, Ray ; Hardy, Melinda Y ; Hart, Derek N J ; Radford, Kristen J ; Vulink, Annelie ; Jongbloed, Sarah L ; Kassianos, Andrew J

Dendritic cells differentiated from monocytes (MoDC) in the presence of GM‐CSF and IL‐15 (IL‐15 MoDC) exhibit superior migration and cytotoxic T‐lymphocyte (CTL) induction compared with MoDC differentiated in IL‐4 and GM‐CSF (IL‐4 MoDC) and are promising candidates for DC immunotherapy. We explored the mechanisms by which IL‐15 MoDC induce CTL. IL‐15 MoDC expressed higher levels of CD40 and secreted high levels of TNF‐α, but little or no IL‐12p70 compared with IL‐4 MoDC. Despite immuno‐selecting monocytes to >97% purity before MoDC generation, a tiny population (0.2%) of natural killer (NK) cells was identified that was increased sevenfold during IL‐15 MoDC, but not IL‐4 MoDC differentiation. These NK cells produced high levels of IFN‐γ and were responsible for the enhanced CTL‐inducing capacity of the IL‐15 MoDC, but not for their increased expression of CD40 or secretion of TNF‐α. Interestingly, a proportion of IL‐15 MoDC were found to express the NK cell marker, CD56, but these did not secrete IFN‐γ. These data implicate a role for small percentages of NK cells in the enhanced capacity of IL‐15 MoDC to induce tumour‐specific CTL independent of IL‐12p70.

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