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J Leukoc Biol. 2019 Jun;105(6):1341-1354. doi: 10.1002/JLB.MA0718-296R. Epub 2019 May 12.

Quantifying NK cell growth and survival changes in response to cytokines and regulatory checkpoint blockade helps identify optimal culture and expansion conditions.

Author information

1
Division of Molecular Immunology, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
2
Department of Medical Biology, University of Melbourne, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Victoria, Australia.
3
Biomedicine Discovery Institute and the Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.

Abstract

NK cells are innate lymphocytes critical for immune surveillance, particularly in eradication of metastatic cancer cells and acute antiviral responses. In contrast to T cells, NK cell-mediated immunity is rapid, with spontaneous cytotoxicity and cytokine/chemokine production upon pathogen detection. The renaissance in cancer immunology has cast NK cell biology back into the spotlight with an urgent need for deeper understanding of the regulatory networks that govern NK cell antitumor activity. To this end, we have adapted and refined a series of quantitative cellular calculus methods, previously applied to T and B lymphocytes, to dissect the biologic outcomes of NK cells following stimulation with cytokines (IL-15, IL-12, IL-18) or deletion of genes that regulate NK cell proliferation (Cish), survival (Bcl2l11), and activation-induced-cell-death (AICD; Fas). Our methodology is well suited to delineate effects on division rate, intrinsic apoptosis, and AICD, permitting variables such as population half-life, rate of cell division, and their combined influence on population numbers in response to stimuli to be accurately measured and modelled. Changes in these variables that result from gene deletion, concentration of stimuli, time, and cell density give insight into the dynamics of NK cell responses and serve as a platform to dissect the mechanism of action of putative checkpoints in NK cell activation and novel NK cell immunotherapy agents.

KEYWORDS:

NK cell; checkpoints; culture; cytokines; etc; homeostasis; proliferation; quantification; stimulation; survival

PMID:
31079418
DOI:
10.1002/JLB.MA0718-296R

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