Regulation of murine NK cell exhaustion through the activation of the DNA damage repair pathway

Maite Alvarez, Federico Simonetta, Jeanette Baker, Antonio Pierini, Arielle S. Wenokur, Alyssa R. Morrison, William J Murphy, Robert S. Negrin

Research output: Contribution to journalArticle

Abstract

NK cell exhaustion (NCE) due to sustained proliferation results in impaired NK cell function with loss of cytokine production and lytic activity. Using murine models of chronic NK cell stimulation, we have identified a phenotypic signature of NCE, characterized by upregulation of the terminal differentiation marker KLRG1 and by downregulation of eomesodermin and the activating receptor NKG2D. Chronic stimulation of mice lacking NKG2D resulted in minimal NCE compared with control mice, thus identifying NKG2D as a crucial mediator of NCE. NKG2D internalization and downregulation on NK cells have been previously observed in the presence of tumor cells with high expression of NKG2D ligands (NKG2DL) due to the activation of the DNA damage repair pathways. Interestingly, our study revealed that during NK cell activation, there is an increase of MULT1, an NKG2DL, that correlates with an induction of DNA damage. Treatment with the ATM DNA damage repair pathway inhibitor KU55933 (KU) during activation reduced NCE by improving expression of activation markers and genes involved in cell survival, through sustaining NKG2D expression and preserving cell functionality. Importantly, NK cells expanded ex vivo in the presence of KU displayed increased antitumor efficacy in both NKG2D-dependent and -independent mouse models. Collectively, these data demonstrate that NCE is caused by DNA damage and is regulated, at least in part, by NKG2D. Further, the prevention of NCE is a promising strategy to improve NK cell–based immunotherapy.

Original languageEnglish (US)
Article numbere127729
JournalJCI Insight
Volume4
Issue number14
DOIs
StatePublished - Jan 1 2019

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DNA Repair
Natural Killer Cells
DNA Damage
Down-Regulation
NK Cell Lectin-Like Receptor Subfamily K
Ligands
Differentiation Antigens
Immunotherapy
Transcriptional Activation
Cell Survival
Up-Regulation
Cytokines

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Alvarez, M., Simonetta, F., Baker, J., Pierini, A., Wenokur, A. S., Morrison, A. R., ... Negrin, R. S. (2019). Regulation of murine NK cell exhaustion through the activation of the DNA damage repair pathway. JCI Insight, 4(14), [e127729]. https://doi.org/10.1172/jci.insight.127729

Regulation of murine NK cell exhaustion through the activation of the DNA damage repair pathway. / Alvarez, Maite; Simonetta, Federico; Baker, Jeanette; Pierini, Antonio; Wenokur, Arielle S.; Morrison, Alyssa R.; Murphy, William J; Negrin, Robert S.

In: JCI Insight, Vol. 4, No. 14, e127729, 01.01.2019.

Research output: Contribution to journalArticle

Alvarez, M, Simonetta, F, Baker, J, Pierini, A, Wenokur, AS, Morrison, AR, Murphy, WJ & Negrin, RS 2019, 'Regulation of murine NK cell exhaustion through the activation of the DNA damage repair pathway', JCI Insight, vol. 4, no. 14, e127729. https://doi.org/10.1172/jci.insight.127729
Alvarez M, Simonetta F, Baker J, Pierini A, Wenokur AS, Morrison AR et al. Regulation of murine NK cell exhaustion through the activation of the DNA damage repair pathway. JCI Insight. 2019 Jan 1;4(14). e127729. https://doi.org/10.1172/jci.insight.127729
Alvarez, Maite ; Simonetta, Federico ; Baker, Jeanette ; Pierini, Antonio ; Wenokur, Arielle S. ; Morrison, Alyssa R. ; Murphy, William J ; Negrin, Robert S. / Regulation of murine NK cell exhaustion through the activation of the DNA damage repair pathway. In: JCI Insight. 2019 ; Vol. 4, No. 14.
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