The Interactions of Multiple Cytokines Control NK Cell Maturation
Open accessAbstract
Although NK cells are well known for their cytotoxic functions, they also produce an array of immunoregulatory cytokines and chemokines. During an immune response, NK cells are exposed to complex combinations of cytokines that influence their differentiation and function. In this study, we have examined the phenotypic and functional consequences of exposing mouse NK cells to IL-4, IL-12, IL-15, IL-18, and IL-21 and found that although all factors induced signs of maturation, characterized by decreased proliferation and IFN-γ secretion, distinct combinations induced unique cytokine secretion profiles. In contrast, the immunosuppressive factors IL-10 and TGF-β had little direct effect on NK cell effector functions. Sustained IL-18 signals resulted in IL-13 and GM-CSF production, whereas IL-12 and IL-21 induced IL-10 and TNF-α. Surprisingly, with the exception of IL-21, all cytokines suppressed cytotoxic function of NK cells at the expense of endogenous cytokine production suggesting that “helper-type” NK cells were generated. The cytokine signals also profoundly altered the cell surface phenotype of the NK cells—a striking example being the downregulation of the activating receptor NKG2D by IL-4 that resulted in decreased NKG2D-dependent killing. IL-4 exposure also modulated NKG2D expression in vivo suggesting it is functionally important during immune responses. This study highlights the plasticity of NK cell differentiation and suggests that the relative abundance of cytokines at sites of inflammation will lead to diverse outcomes in terms of NK cell phenotype and interaction with the immune system.
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IL-21 and IL-15 have been proposed to strongly enhance NK cell-mediated immunity against cancer cells.
“The cytokines IL-21 and IL-15 have been suggested to substantially boost NK cell-mediated immunity against cancer cells222–225.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [223]
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- Authors
- Brady, J., Carotta, S., Thong, R. P. L., Chan, C. J., Hayakawa, Y., Smyth, M. J., & Nutt, S. L.
- Affiliations
- Walter and Eliza Hall Institute of Medical Research (AU)
- Peter MacCallum Cancer Centre (AU)
- Corresponding author
- Brady, Jason
- Carotta, Sebastian
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-12-01
- Volume
- 185
- Issue
- 11
- Pages
- 6679-6688
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W1920719117
- Cited by
- 130
- References
- 64
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 13 · 2023: 8 · 2022: 4 · 2021: 6 · 2020: 11 · 2019: 12 · 2018: 6 · 2017: 4 · 2016: 7 · 2015: 10 · 2014: 15 · 2013: 6 · 2012: 8
- FWCI
- 3.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Pfizer
- Pfizer Australia
- University of Toronto
- Medical Research Council
- National Health and Medical Research Council
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
- Keywords
- NK cell maturation, cytokine interactions, IL-4, IL-12, IL-15, IL-18, IL-21, IL-10, TGF-beta, NKG2D, NK cell cytotoxicity, interferon-gamma
- MeSH terms
- Animals, Cell Differentiation, Cells, Cultured, Cytotoxicity Tests, Immunologic, Humans, Killer Cells, Natural, Membrane Proteins, Mice, Inbred C57BL, Signal Transduction, Immunophenotyping, Cytokines, Mice, Knockout, Homeodomain Proteins, Inflammation Mediators, Mice
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