| Title: |
NK Cell Priming From Endogenous Homeostatic Signals Is Modulated by CIS |
| Authors: |
Delconte, RB; Guittard, G; Goh, W; Hediyeh-Zadeh, S; Hennessy, RJ; Rautela, J; Davis, MJ; Souza-Fonseca-Guimaraes, F; Nunès, JA; Huntington, ND |
| Publisher Information: |
FRONTIERS MEDIA SA |
| Publication Year: |
2020 |
| Collection: |
The University of Melbourne: Digital Repository |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| ISSN: |
1664-3224 |
| Relation: |
https://hdl.handle.net/11343/245660 |
| Availability: |
https://hdl.handle.net/11343/245660 |
| Rights: |
https://creativecommons.org/licenses/by/4.0 ; CC BY |
| Accession Number: |
edsbas.FEE98A8F |
| Database: |
BASE |