Functional NK cell repertoires are maintained through IL-2Rα and fas ligand

Martin Felices, Todd R. Lenvik, Dave E M Ankarlo, Bree Foley, Julie Curtsinger, Xianghua Luo, Bruce R. Blazar, Stephen K. Anderson, Jeffrey S. Miller

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Acquisition of a functional NK cell repertoire, known as education or licensing, is a complex process mediated through inhibitory receptors that recognize self.We found that NK cells containing self-killer Ig-like receptors for cognate HLA ligand in vivo were less susceptible to apoptosis. In vitro IL-15 withdrawal showed that uneducated NK cells upregulated Bim and Fas. Conversely, educated NK cells upregulated Fas ligand (FasL) under these conditions. Induction of cell death and Bim expression on uneducated cells correlated with increased IL-2Rα expression. Overexpression and knockdown studies showed that higher IL-2Rα limits NK cell survival in a novel manner that is independent from the role of IL-2 in activation-induced cell death. To study the role of FasL in induction of IL-2Rαhi NK cell death, a coculture assay with FasL-blocking Abs was used. IL-15 withdrawal led to FasL-dependent killing of IL-2Rα hi NK cells by more educated IL-2Rα lo NK cells. Finally, CMV reactivation induces a potent long-lasting population of licensed NK cells with enhanced survival. These findings show that education-dependent NK cell survival advantages and killing of uneducated NK cells result in the maintenance of a functional repertoire, which may be manipulated to exploit NK cells for cancer immunotherapy.

Original languageEnglish (US)
Pages (from-to)3889-3897
Number of pages9
JournalJournal of Immunology
Volume192
Issue number8
DOIs
StatePublished - Apr 15 2014

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