IL-12 regulates the expansion, phenotype, and function of murine NK cells activated by IL-15 and IL-18.
Animals
Cell Line
Cell Proliferation
/ physiology
Cytotoxicity, Immunologic
/ immunology
Interleukin-12
/ immunology
Interleukin-15
/ immunology
Interleukin-18
/ immunology
Killer Cells, Natural
/ immunology
Male
Mice
Mice, Knockout
Phenotype
Signal Transduction
/ immunology
T-Lymphocytes
/ immunology
Cancer immunotherapy
Cytokines
Innate lymphoid cells
NK cell differentiation
NK cell proliferation
Journal
Cancer immunology, immunotherapy : CII
ISSN: 1432-0851
Titre abrégé: Cancer Immunol Immunother
Pays: Germany
ID NLM: 8605732
Informations de publication
Date de publication:
Sep 2020
Sep 2020
Historique:
received:
20
03
2019
accepted:
19
03
2020
pubmed:
26
4
2020
medline:
18
8
2020
entrez:
26
4
2020
Statut:
ppublish
Résumé
NK cells, which are composed of phenotypically and functionally heterogeneous subpopulations, play critical roles in immunity against cancer. The mechanism of generation of distinct subsets such as the effector and regulatory subtypes is unclear. Here, we show that this process comprises several steps, including generation of proliferating, highly cytotoxic cells activated by IL-15/IL-18 and differentiation into distinct cell populations induced with IL-12. Freshly prepared murine splenic NK cells expressed IL-15Rs and IL-18Rs and rapidly began to proliferate following stimulation with IL-15/IL-18. The proliferating NK cells highly expressed various activation markers such as B220, CD49b (DX5), lysosome-associated membrane glycoprotein 1 (LAMP-1), DNAX accessory molecule 1, perforin, and granzyme B and showed reduced expression of natural killer cell p46-related protein (NKp46) and IL-18Rα. These cells exerted strong cytotoxicity against YAC-1 cells, but did not secrete cytokines. IL-12 rapidly activated STAT4 in these cells, induced IFN-γ production, and then upregulated p21 and p27, leading to withdrawal from the cell cycle. In parallel, IL-12-stimulated cells gradually reduced cytotoxicity, decreased expression of activation markers, and instead increased expression of Sca-1, CD25, CD49a, and NKp46. Some IL-15/IL-18-induced cells strongly expressed PD-1, whereas NK cells induced with IL-15/IL-18 and IL-12 expressed high levels of T cell immunoglobulin mucin-3, LAG-3, and natural killer group 2 A. Furthermore, these cells spontaneously secreted IL-10 and TGF-β following prolonged incubation. Thus, IL-12 regulates expansion of NK cells activated with IL-15/IL-18, influences the population size of highly cytotoxic cells, and induces differentiation to unique cells sharing some phenotypes of ILCs.
Identifiants
pubmed: 32333080
doi: 10.1007/s00262-020-02553-4
pii: 10.1007/s00262-020-02553-4
doi:
Substances chimiques
Interleukin-15
0
Interleukin-18
0
Interleukin-12
187348-17-0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1699-1712Subventions
Organisme : Japan Society for the Promotion of Science, KAKENHI
ID : JP25462671
Organisme : Japan Society for the Promotion of Science, KAKENHI
ID : JP16K11220
Organisme : Japan Agency for Medical Research and Development
ID : JP18nk0101355h0102
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