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−CD56 dim CD57 + 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.
Bibliographical noteFunding Information:
This work was supported by grants from the National Institutes of Health (K99HL123638 to F. Cichocki, CA111412 to B.R. Bla-zar and J.S. Miller, CA65493 to B.R. Blazar and J.S. Miller, CA197292 to M. Felices and J.S. Miller, HL122216 to J.S. Miller, HL11879, and P01 CA142106 to B.R. Blazar), the European Research Council under the European Union’s Seventh Framework Program (FP/2007-2013)/ERC Grant Agreement no. 311335, the Swedish Research Council, Norwegian Research Council, Swedish Foundation for Strategic Research, Wallenberg Foundation, Swedish Cancer Foundation, and the Swedish Childhood Cancer Foundation, as well as the Stockholm County Council and Karolinska Institutet Center for Innovative Medicine (to Y.T. Bryceson). The authors declare no competing financial interests.