Cutting Edge: Differential Fine-Tuning of IL-2- and IL-15-Dependent Functions by Targeting Their Common IL-2/15Rβ/γc Receptor

• Published in: The Journal of immunology (1950) 2017-06, Vol.198 (12), p.4563-4568
• Main Authors: Meghnem, Dihia, Morisseau, Sébastien, Frutoso, Marie, Trillet, Kilian, Maillasson, Mike, Barbieux, Isabelle, Khaddage, Sarah, Leray, Isabelle, Hildinger, Markus, Quéméner, Agnès, Jacques, Yannick, Mortier, Erwan
• Format: Article
• Language: English
• Subjects: Animals; Cancer; CD122 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cell Line; Cell Proliferation; Cytokines; Humans; Immune system; Interleukin 15; Interleukin 2; Interleukin 2 receptors; Interleukin Receptor Common gamma Subunit - genetics; Interleukin Receptor Common gamma Subunit - immunology; Interleukin Receptor Common gamma Subunit - metabolism; Interleukin-15 - antagonists & inhibitors; Interleukin-15 - immunology; Interleukin-15 - metabolism; Interleukin-15 Receptor alpha Subunit - genetics; Interleukin-15 Receptor alpha Subunit - immunology; Interleukin-15 Receptor alpha Subunit - metabolism; Interleukin-2 - antagonists & inhibitors; Interleukin-2 - immunology; Interleukin-2 - metabolism; Interleukin-2 Receptor alpha Subunit - genetics; Interleukin-2 Receptor alpha Subunit - immunology; Interleukin-2 Receptor alpha Subunit - metabolism; Interleukin-2 Receptor beta Subunit - genetics; Interleukin-2 Receptor beta Subunit - immunology; Killer Cells, Natural - immunology; Life Sciences; Lymphocyte Activation - immunology; Lymphocytes T; Mice; Protein Binding; Signal Transduction - immunology; T-Lymphocytes, Regulatory - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1700046

Interleukin 2 and IL-15 are two closely related cytokines, displaying important functions in the immune system. They share the heterodimeric CD122/CD132 receptor to deliver their signals within target cells. Their specificity of action is conferred by their α receptor chains, IL-2Rα and IL-15Rα. By combining an increased affinity for CD122 and an impaired recruitment of CD132, we have generated an original molecule named IL-2Rβ/γ (CD122/CD132) inhibitor (BiG), targeting the CD122/CD132 receptor. BiG efficiently inhibited IL-15- and IL-2-dependent functions of primary cells, including CD8 T and NK cells, in vitro and in vivo. We also report a differential dynamic of action of these cytokines by highlighting a major role played by the IL-2Rα receptor. Interestingly, due to the presence of IL-2Rα, BiG had no impact on IL-2-dependent regulatory T cell proliferation. Thus, by acting as a fine switch in the immune system, BiG emphasizes the differential roles of these two cytokines.