NK Cell Priming From Endogenous Homeostatic Signals Is Modulated by CIS

Rebecca B. Delconte, Geoffrey Guittard, Wilford Goh, Soroor Hediyeh-Zadeh, Robert J. Hennessy, Jai Rautela, Melissa J. Davis, Fernando Souza-Fonseca-Guimaraes, Jacques A. Nunès, Nicholas D. Huntington

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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 languageEnglish
Article number75
Number of pages16
JournalFrontiers in Immunology
Publication statusPublished - 31 Jan 2020


  • CIS
  • Homeostasis
  • IL-15
  • NK cell
  • priming

Cite this

Delconte, R. B., Guittard, G., Goh, W., Hediyeh-Zadeh, S., Hennessy, R. J., Rautela, J., Davis, M. J., Souza-Fonseca-Guimaraes, F., Nunès, J. A., & Huntington, N. D. (2020). NK Cell Priming From Endogenous Homeostatic Signals Is Modulated by CIS. Frontiers in Immunology, 11, [75]. https://doi.org/10.3389/fimmu.2020.00075