NK Cell Priming From Endogenous Homeostatic Signals Is Modulated by CIS
Date
2020
Authors
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.
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Journal article
Citation
Frontiers in Immunology, 2020; 11:1-16
Statement of Responsibility
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, and Nicholas D. Huntington
Conference Name
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.
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© 2020 Delconte, Guittard, Goh, Hediyeh-Zadeh, Hennessy, Rautela, Davis, Souza-Fonseca-Guimaraes, Nunès and Huntington. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
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http://purl.org/au-research/grants/nhmrc/1124788
http://purl.org/au-research/grants/nhmrc/1124784
http://purl.org/au-research/grants/nhmrc/1088703
http://purl.org/au-research/grants/nhmrc/1140406
http://purl.org/au-research/grants/nhmrc/1066770
http://purl.org/au-research/grants/nhmrc/1124907
http://purl.org/au-research/grants/nhmrc/1158615
http://purl.org/au-research/grants/nhmrc/1057852
http://purl.org/au-research/grants/nhmrc/1124784
http://purl.org/au-research/grants/nhmrc/1088703
http://purl.org/au-research/grants/nhmrc/1140406
http://purl.org/au-research/grants/nhmrc/1066770
http://purl.org/au-research/grants/nhmrc/1124907
http://purl.org/au-research/grants/nhmrc/1158615
http://purl.org/au-research/grants/nhmrc/1057852