NK cell priming from endogenous homeostatic signals is modulated by CIS
- Author(s)
- Delconte, RB; Guittard, G; Goh, W; Hediyeh-Zadeh, S; Hennessy, RJ; Rautela, J; Davis, MJ; Souza-Fonseca-Guimaraes, F; Nunes, JA; Huntington, ND;
- Journal Title
- Frontiers in Immunology
- Publication Type
- Journal Article
- Abstract
- 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.
- Publisher
- Frontiers Media
- Research Division(s)
- Immunology; Bioinformatics
- PubMed ID
- 32082327
- Publisher's Version
- https://doi.org/10.3389/fimmu.2020.00075
- Open Access at Publisher's Site
https://doi.org/10.3389/fimmu.2020.00075- Terms of Use/Rights Notice
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Creation Date: 2020-05-04 11:46:54
Last Modified: 2020-05-04 02:13:16