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PMID: 30061358 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

ARID5B regulates metabolic programming in human adaptive NK cells.

The Journal of experimental medicine ·Vol. 215 ·No. 9 ·2018-00-03 ·Pages 2379-2395

Cichocki F, Wu CY, Zhang B, Felices M, Tesi B, Tuininga K, Dougherty P, Taras E, Hinderlie P, Blazar BR, Bryceson YT, Miller JS

Abstract

Natural killer (NK) cells with adaptive immunological properties expand and persist in response to human cytomegalovirus. Here, we explored the metabolic processes unique to these cells. Adaptive CD3-CD56dimCD57+NKG2C+ NK cells exhibited metabolic hallmarks of lymphocyte memory, including increased oxidative mitochondrial respiration, mitochondrial membrane potential, and spare respiratory capacity. Mechanistically, we found that a short isoform of the chromatin-modifying transcriptional regulator, AT-rich interaction domain 5B (ARID5B), was selectively induced through DNA hypomethylation in adaptive NK cells. Knockdown and overexpression studies demonstrated that ARID5B played a direct role in promoting mitochondrial membrane potential, expression of genes encoding electron transport chain components, oxidative metabolism, survival, and IFN-γ production. Collectively, our data demonstrate that ARID5B is a key regulator of metabolism in human adaptive NK cells, which, if targeted, may be of therapeutic value.

MeSH Terms
Cell Survival/genetics,immunology Cytomegalovirus/immunology,metabolism Cytomegalovirus Infections/genetics,immunology,metabolism,pathology DNA-Binding Proteins/genetics,immunology,metabolism Female Humans Interferon-gamma/biosynthesis,genetics,immunology K562 Cells Killer Cells, Natural/immunology,metabolism,pathology Lymphocyte Activation Male Membrane Potential, Mitochondrial/genetics,immunology Oxidation-Reduction Transcription Factors/genetics,immunology,metabolism
Chemicals
ARID5B protein, human DNA-Binding Proteins IFNG protein, human Transcription Factors Interferon-gamma
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Cichocki Frank
Department of Medicine, University of Minnesota, Minneapolis, MN.
Wu Cheng-Ying
Department of Medicine, University of Minnesota, Minneapolis, MN.
Zhang Bin ORCID
Department of Medicine, University of Minnesota, Minneapolis, MN.
Felices Martin
Department of Medicine, University of Minnesota, Minneapolis, MN.
Tesi Bianca
Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden. | Clinical Genetics Unit, Department of Molecular Medicine and Surgery, and Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
Tuininga Katie
Department of Medicine, University of Minnesota, Minneapolis, MN.
Dougherty Phillip
Department of Medicine, University of Minnesota, Minneapolis, MN.
Taras Emily
Department of Medicine, University of Minnesota, Minneapolis, MN.
Hinderlie Peter
Department of Medicine, University of Minnesota, Minneapolis, MN.
Blazar Bruce R ORCID
Department of Pediatrics, University of Minnesota, Minneapolis, MN.
Bryceson Yenan T ORCID
Centre for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden. | Broegelmann Research Laboratory, Department of Clinical Sciences, University of Bergen, Bergen, Norway.
Miller Jeffrey S ORCID
Department of Medicine, University of Minnesota, Minneapolis, MN mille011@umn.edu.
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
1540-9538
DOI
10.1084/jem.20172168
Email
mille011@umn.edu
Published
2018-00-03
Epub
2018-00-30
Pages
2379-2395
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC6122973
Subset
IM
Grants
NHLBI NIH HHS · R00 HL123638 · United States
NCI NIH HHS · P30 CA077598 · United States
NCI NIH HHS · P01 CA065493 · United States
NHLBI NIH HHS · R01 HL118979 · United States
NHLBI NIH HHS · R01 HL122216 · United States
NCI NIH HHS · R35 CA197292 · United States
NCI NIH HHS · P01 CA111412 · United States
NCI NIH HHS · R01 CA072669 · United States
NCI NIH HHS · P01 CA142106 · United States
NHLBI NIH HHS · K99 HL123638 · United States
Databases
RefSeq
NM_032199
External Links
PubMed source DOI: 10.1084/jem.20172168 PMC Full Text View journal details
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