The Helix-Loop-Helix Protein ID2 Governs NK Cell Fate by Tuning Their Sensitivity to Interleukin-15

RB Delconte; W Shi; P Sathe; T Ushiki; C Seillet; M Minnich; TB Kolesnik; LC Rankin; LA Mielke; JG Zhang; M Busslinger; MJ Smyth; DS Hutchinson; SL Nutt; SE Nicholson; WS Alexander; LM Corcoran; E Vivier; GT Belz; S Carotta; ND Huntington

Journal article

The Helix-Loop-Helix Protein ID2 Governs NK Cell Fate by Tuning Their Sensitivity to Interleukin-15

RB Delconte, W Shi, P Sathe, T Ushiki, C Seillet, M Minnich, TB Kolesnik, LC Rankin, LA Mielke, JG Zhang, M Busslinger, MJ Smyth, DS Hutchinson, SL Nutt, SE Nicholson, WS Alexander, LM Corcoran, E Vivier, GT Belz, S Carotta Show all

Immunity | Published : 2016

DOI: 10.1016/j.immuni.2015.12.007

Abstract

The inhibitor of DNA binding 2 (Id2) is essential for natural killer (NK) cell development with its canonical role being to antagonize E-protein function and alternate lineage fate. Here we have identified a key role for Id2 in regulating interleukin-15 (IL-15) receptor signaling and homeostasis of NK cells by repressing multiple E-protein target genes including Socs3. Id2 deletion in mature NK cells was incompatible with their homeostasis due to impaired IL-15 receptor signaling and metabolic function and this could be rescued by strong IL-15 receptor stimulation or genetic ablation of Socs3. During NK cell maturation, we observed an inverse correlation between E-protein target genes and Id..

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University of Melbourne Researchers

Rebecca Delconte Author

Cyril Seillet Author

Lucille. C. Rankin Author

Stephen Nutt Author

Grants

Awarded by Seventh Framework Programme

Funding Acknowledgements

We wish to thank Tobias Kratina, Tania Camilleri, Pradnya Gangatirkar, Hesham Abdulla, Cathy Quillici, and Mary Camilleri for technical assistance and Andreas Strasser, Ross Dickins, and Philippe Bouillet for reagents and helpful discussion. We thank the staff of the WEHI Animal Services, monoclonal antibody facility, the flow cytometry facility, and Clinical Translational Centre. This work is supported by program and project grants from the National Health and Medical Research Council (NH&MRC) of Australia (1027472 to S.C., N.D.H., and G.T.B.; 1047903 to G.T.B. and L.A.M.; 1016647 to J.-G.Z., S.E.N., and W.S.A.; 1049407, 1066770, 1057852 to N.D.H.). This work is supported by fellowships from the National Health and Medical Research Council of Australia (GNT0461276 to N.D.H.; 1058344 to W.S.A.; 545952 to D.S.H.; Dora Lush Training Scholarship to L.C.R.), the Australian Research Council (S.C., G.T.B., S.L.N.), Australia Fellowship (628623) to M.J.S., Cancer Australia (L.A.M.), and The Menzies Foundation (N.D.H.). R.B.D. is supported by a Leukaemia Foundation scholarship. The E.V. lab is supported by the European Research Council (THINK Advanced Grant) and by institutional grants from INSERM, CNRS, and Aix Marseille to CIML. E.V. is a scholar of the Institut Universitaire de France. The M.B. group was supported by Boehringer Ingelheim and an ERC Advanced Grant (291740 - Lymphocyte Control) from the European Community's Seventh Framework Program. This study was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC Independent Research Institute Infrastructure Support scheme.