High dose CD11c-driven IL15 is sufficient to drive NK cell maturation and anti-tumor activity in a trans-presentation independent manner

Abstract

The common gamma (γc)-chain cytokine interleukin 15 (IL15) is a multifunctional immune-modulator which impacts the generation, maturation and activity of many cell types of the innate, as well as the adaptive immune system, including natural killer (NK) and CD8+ T cells. Using a new series of transgenic mice, we analyzed the in vivo potential of IL15 as an immune-regulator when available at different concentrations or delivery modes, i.e. soluble monomer or complexed to its specific receptor α (Rα)-chain. We have identified distinct effects on selected IL15-responsive populations. While CD8+ T cells required complexed forms of IL15/IL15Rα for full functionality, mature NK populations were rescued in an IL15/IL15Rα-deficient environment by high levels of CD11c-restricted IL15. These IL15-conditions were sufficient to limit tumor formation in a lung metastasis model indicating that the NK cell populations were fully functional. These data underline the potential of “free” IL15 in the absence of Rα-complex as a powerful and specific immuno-modulator, which may be beneficial where selective immune-activation is desired.

Group 1 Innate Lymphoid Cell Lineage Identity Is Determined by a cis-Regulatory Element Marked by a Long Non-coding RNA

“…Following the production of new NK cells in the bone marrow, immature NK cells undergo a maturation process driven by the cytokine IL-15, which is characterized by the acquisition of the surface marker CD11b, loss of CD27, and increased proliferation and survival (Figure 3F) (Chiossone et al, 2009; Polansky et al., 2016). Ablation of the Rroid locus resulted in a block of NK cell maturation characterized by accumulation of immature CD27 + NK cells and a near complete loss of mature CD11b + NK cells (Figure 3F–G).…”

Discovery and characterization of a novel humanized anti-IL-15 antibody and its relevance for the treatment of refractory celiac disease and eosinophilic esophagitis

“…5,49,50 Indeed, as speculated earlier, 4 it is possible that in inflammatory conditions an increase in IL-15 production could override the mechanism of trans presentation. 51,52 Moreover, the presumably prominent role of trans presentation is supported by the hypothesis that IL-15 in the circulation predominantly, if not only, exists as a heterodimer with IL-15Ra. 38 This is, however, not always the case, as we demonstrate here that intranasal Aspergillus administration to mice triggers an increase in both free and IL-15Ra-bound IL-15 circulating levels.…”

CD215+ Myeloid Cells Respond to Interleukin 15 Stimulation and Promote Tumor Progression

“…However, there are other reports indicating that IL-15 also participates in the growth and survival of malignant cells in hematopoietic malignancies and solid tumors ( 20 , 21 , 61 , 62 ). The protumoral activity of IL-15 may be underestimated since most of the analyses to study IL-15 function are using immune-sufficient mice and focus on its effect on CD8 T cells or NK cells ( 12 , 13 , 16 , 17 ). However, it has been reported that GM-CSF and IL-15 fusokine is an immunosuppressor and allow engraftment of allogeneic B16F10 in immunocompetent mice ( 62 ).…”

“…IL-15 exhibits broad activity and induces the differentiation and proliferation of lymphocytes ( 1 , 7 ) and myelocytes ( 8 , 9 ). The studies of mutant mice deficient in IL-15 or IL-15Rα suggest that IL-15 play a multifaceted role in the development and control of the immune system ( 10 – 13 ). Thus, IL-15 has become a promising candidate for tumor immunotherapy; IL-15 administration is used to bolster immune responses ( 14 , 15 ) and augment the tumor immune surveillance ( 16 , 17 ).…”