Homeostasis of Human NK Cells Is Not IL-15 Dependent

Abstract

IL-15 is a proinflammatory cytokine that plays an important role in the development and activation of NK cells and is a potential target for inflammatory disease therapy. Studies conducted in IL-15- and IL-15R knockout mice identified IL-15 as an important cytokine for NK cell homeostasis. Consistent with this information derived from genetically modified mice, we demonstrated that neutralizing IL-15 with a mouse anti-mouse IL-15 mAb (M96) depletes C57BL/6 mouse NK cells. An mAb directed against macaque IL-15 (Hu714MuXHu) was manufactured and demonstrated to block IL-15–induced activation of nonhuman primate (NHP) NK cells in vitro. Neutralization of macaque IL-15 by parenteral administration of Hu714MuXHu reduces (>95%) circulating NK cell counts in NHPs. A blocking mAb directed against human IL-15 (huIL-15; AMG 714) was manufactured. Unexpectedly, when human subjects were treated with the blocking anti–IL-15 Ab AMG 714 in clinical trials, no reductions in circulating NK cell counts were observed despite achieving significantly higher exposures than the levels of Hu714MuXHu needed to cause NK cell count reductions in NHPs in vivo. Both AMG 714 and Hu714MuXHu are able to block huIL-15 activity in a human T cell blast proliferation and IFN-γ production assay. Both Abs block huIL-15–mediated Stat5 activation and CD69 expression in human NK cells. Collectively, these results demonstrate that NK cell homeostasis is obligatorily dependent upon IL-15 in both mice and NHPs, but that IL-15 is dispensable for maintenance of circulating human NK cells.

Enzymatic synthesis of core 2 O-glycans governs the tissue-trafficking potential of memory CD8 + T cells

“…To investigate whether steady-state exposure to IL-15 maintained the synthesis of selectin ligands on memory CD8 + T cells, we utilized an IL-15 neutralizing antibody (27). Indeed, neutralizing IL-15 caused circulating memory CD8 + T cells to reduce binding to E- and P-selectin, but did not affect the circulating frequency (Fig 2G–I).…”

Effect of Anti–IL-15 Administration on T Cell and NK Cell Homeostasis in Rhesus Macaques

“…This mAb was based on the mouse, anti-human IL-15 mAb clone, M111, which is cross-reactive with RM IL-15 (66). Rhesusization was accomplished by exchanging the mouse amino acid sequences in the constant regions and variable binding surfaces for rhesus amino acid sequences, leaving variable region sequences responsible for IL-15 recognition unchanged (67, 68).…”

NK cells activated by Interleukin-4 in cooperation with Interleukin-15 exhibit distinctive characteristics

“…Because the IL-4Rα KO mouse was nonresponsive to both IL-4 and -13, we also investigated the role of IL-13 for NK cells and found that overexpression of IL-13 did not induce IL4-NK cells (Fig. S4) (19)(20)(21). Therefore, we examined macrophages in the liver and found that macrophages were remarkably increased in the mice overexpressing IL-4 compared with control mice by immunohistochemical staining (Fig.…”