NK Cell Priming From Endogenous Homeostatic Signals Is Modulated by CIS.
Natural killer (NK) cell activation is controlled by a balance of activating and inhibitory signals and cytokines such as IL-15. We previously identified cytokine-inducible SH2-containing protein (CIS) as a negative regulator of IL-15 signaling in NK cells under inflammatory conditions. While the functional effect of Cish-deficiency in NK cells was obvious by their increased anti-tumor immunity and hyper-proliferative response to IL-15, it remained unclear how CIS regulates NK cell biology in steady-state. Here, we investigated the role of CIS in the homeostatic maintenance of NK cells and found CIS-ablation promoted terminal differentiation of NK cells and increased turnover, suggesting that under steady-state conditions, CIS plays a role in maintaining IL-15 driven regulation of NK cells in vivo. However, hyper-responsiveness to IL-15 did not manifest in NK cell accumulation, even when the essential NK cell apoptosis mediator, Bcl2l11 (BIM) was deleted in addition to Cish. Instead, loss of CIS conferred a lower activation threshold, evidenced by augmented functionality on a per cell basis both in vitro and in vivo without prior priming. We conclude that Cish regulates IL-15 signaling in NK cells in vivo, and through the rewiring of several activation pathways leads to a reduction in activation threshold, decreasing the requirement for priming and improving NK cell anti-tumor function. Furthermore, this study highlights the tight regulation of NK cell homeostasis by several pathways which prevent NK cell accumulation when IL-15 signaling and intrinsic apoptosis are dysregulated.
['Delconte|Rebecca B|RB|', 'Guittard|Geoffrey|G|', 'Goh|Wilford|W|', 'Hediyeh-Zadeh|Soroor|S|', 'Hennessy|Robert J|RJ|', 'Rautela|Jai|J|', 'Davis|Melissa J|MJ|', 'Souza-Fonseca-Guimaraes|Fernando|F|', 'Nunès|Jacques A|JA|', 'Huntington|Nicholas D|ND|']
D000818:Animals D002454:Cell Differentiation D006706:Homeostasis D019409:Interleukin-15 D007694:Killer Cells, Natural D008213:Lymphocyte Activation D051379:Mice D008810:Mice, Inbred C57BL D018345:Mice, Knockout D050826:Suppressor of Cytokine Signaling Proteins
NK cell priming CIS IL-15 Homeostasis