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Quantifying NK cell growth and survival changes in response to cytokines and regulatory checkpoint blockade helps identify optimal culture and expansion conditions
Author(s) -
Hennessy Robert J.,
Pham Kim,
Delconte Rebecca,
Rautela Jai,
Hodgkin Philip D,
Huntington Nicholas D.
Publication year - 2019
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1002/jlb.ma0718-296r
Subject(s) - biology , immunology , population , cancer immunotherapy , chemokine , immune system , microbiology and biotechnology , immunotherapy , cancer research , medicine , environmental health
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.