Selective Targeting of IL-15Rα Is Sufficient to Reduce Inflammation.

Dihia Meghnem, Mike Maillasson, Isabelle Barbieux, Sébastien Morisseau, Dalloba Keita, Yannick Jacques, Agnès Quéméner, Erwan Mortier

Frontiers in immunology 2022

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Cytokines are crucial molecules for maintaining the proper functioning of the immune system. Nevertheless, a dysregulation of cytokine expression could be involved in the pathogenesis of autoimmune diseases. Interleukin (IL)-15 is a key factor for natural killer cells (NK) and CD8 T cells homeostasis, necessary to fight cancer and infections but could also be considered as a pro-inflammatory cytokine involved in autoimmune inflammatory disease, including rheumatoid arthritis, psoriasis, along with tumor necrosis factor alpha (TNF-α), IL-6, and IL-1β. The molecular mechanisms by which IL-15 exerts its inflammatory function in these diseases are still unclear. In this study, we generated an IL-15-derived molecule called NANTIL-15 (New ANTagonist of IL-15), designed to selectively inhibit the action of IL-15 through the high-affinity trimeric IL-15Rα/IL-2Rβ/γc receptor while leaving IL-15 signaling through the dimeric IL-2Rβ/γc receptor unaffected. Administrating of NANTIL-15 in healthy mice did not affect the IL-15-dependent cell populations such as NK and CD8 T cells. In contrast, we found that NANTIL-15 efficiently reduced signs of inflammation in a collagen-induced arthritis model. These observations demonstrate that the inflammatory properties of IL-15 are linked to its action through the trimeric IL-15Rα/IL-2Rβ/γc receptor, highlighting the interest of selectively targeting this receptor. Copyright © 2022 Meghnem, Maillasson, Barbieux, Morisseau, Keita, Jacques, Quéméner and Mortier.

Citation

Dihia Meghnem, Mike Maillasson, Isabelle Barbieux, Sébastien Morisseau, Dalloba Keita, Yannick Jacques, Agnès Quéméner, Erwan Mortier. Selective Targeting of IL-15Rα Is Sufficient to Reduce Inflammation. Frontiers in immunology. 2022;13:886213