Projects per year
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.
Original language | English |
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Article number | 75 |
Number of pages | 16 |
Journal | Frontiers in Immunology |
Volume | 11 |
DOIs | |
Publication status | Published - 31 Jan 2020 |
Keywords
- CIS
- Homeostasis
- IL-15
- NK cell
- priming
Projects
- 2 Finished
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Identification of CIS as a potent checkpoint in NK cell-mediated tumour immunity
Huntington, N. (Primary Chief Investigator (PCI)), Smyth, M. J. (Chief Investigator (CI)), Vivier, É. (Chief Investigator (CI)) & Nicholson, S. E. (Chief Investigator (CI))
NHMRC - National Health and Medical Research Council (Australia)
1/06/19 → 31/12/20
Project: Research
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Identification and targeting of a potent NK cell “checkpoint” in tumour immunity
Huntington, N. (Primary Chief Investigator (PCI))
NHMRC - National Health and Medical Research Council (Australia)
1/02/19 → 31/12/20
Project: Research