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Journal Articles Frontiers in Immunology Year : 2022

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

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Abstract

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-a), IL-6, and IL-1b. 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-15Ra/IL-2Rb/gc receptor while leaving IL-15 signaling through the dimeric IL-2Rb/gc 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-15Ra/IL-2Rb/gc receptor, highlighting the interest of selectively targeting this receptor.
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inserm-03672135 , version 1 (19-05-2022)

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Dihia Meghnem, Mike Maillasson, Isabelle Barbieux, Sébastien Morisseau, Dalloba Keita, et al.. Selective Targeting of IL-15Rα Is Sufficient to Reduce Inflammation. Frontiers in Immunology, 2022, 13, pp.886213. ⟨10.3389/fimmu.2022.886213⟩. ⟨inserm-03672135⟩
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