{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T14:57:04Z","timestamp":1791385024589,"version":"4.3.3"},"reference-count":57,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2024,4,23]],"date-time":"2024-04-23T00:00:00Z","timestamp":1713830400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["22-15-00503"],"award-info":[{"award-number":["22-15-00503"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>HLA-DR-positive NK cells, found in both healthy individuals and patients with different inflammatory diseases, are characterized as activated cells. However, data on their capacity for IFN\u03b3 production or cytotoxic response vary between studies. Thus, more precise investigation is needed of the mechanisms related to the induction of HLA-DR expression in NK cells, their associations with NK cell differentiation stage, and functional or metabolic state. In this work, HLA-DR-expressing NK cell subsets were investigated using transcriptomic analysis, metabolic activity assays, and analysis of intercellular signaling cascades. We demonstrated that HLA-DR+CD56bright NK cells were characterized by a proliferative phenotype, while HLA-DR+CD56dim NK cells exhibited features of adaptive cells and loss of inhibitory receptors with increased expression of MHC class II trans-activator CIITA. The activated state of HLA-DR-expressing NK cells was confirmed by higher levels of ATP and mitochondrial mass observed in this subset compared to HLA-DR\u2212 cells, both ex vivo and after stimulation in culture. We showed that HLA-DR expression in NK cells in vitro can be induced both through stimulation by exogenous IL-2 and IL-21, as well as through auto-stimulation by NK-cell-produced IFN\u03b3. At the intracellular level, HLA-DR expression depended on the activation of STAT3- and ERK1\/2-mediated pathways, with subsequent activation of isoform 3 of the transcription factor CIITA. The obtained results broaden the knowledge about HLA-DR-positive NK cell appearance, diversity, and functions, which might be useful in terms of understanding the role of this subset in innate immunity and assessing their possible implications in NK cell-based therapy.<\/jats:p>","DOI":"10.3390\/ijms25094609","type":"journal-article","created":{"date-parts":[[2024,4,23]],"date-time":"2024-04-23T10:34:05Z","timestamp":1713868445000},"page":"4609","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["HLA-DR Expression in Natural Killer Cells Marks Distinct Functional States, Depending on Cell Differentiation Stage"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6365-0279","authenticated-orcid":false,"given":"Sofya A.","family":"Kust","sequence":"first","affiliation":[{"name":"Shemyakin & Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3378-6508","authenticated-orcid":false,"given":"Maria O.","family":"Ustiuzhanina","sequence":"additional","affiliation":[{"name":"Shemyakin & Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5403-0753","authenticated-orcid":false,"given":"Maria A.","family":"Streltsova","sequence":"additional","affiliation":[{"name":"Shemyakin & Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0120-9319","authenticated-orcid":false,"given":"Pavel V.","family":"Shelyakin","sequence":"additional","affiliation":[{"name":"Abu Dhabi Stem Cells Center, Abu Dhabi 4600, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maxim A.","family":"Kryukov","sequence":"additional","affiliation":[{"name":"Shemyakin & Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"},{"name":"Federal State Autonomous Institution, N.N. Burdenko National Medical Research Center of Neurosurgery, the Ministry of Health of the Russian Federation, 125047 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gennady V.","family":"Lutsenko","sequence":"additional","affiliation":[{"name":"Shemyakin & Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5820-5947","authenticated-orcid":false,"given":"Anna V.","family":"Sudarikova","sequence":"additional","affiliation":[{"name":"Federal State Autonomous Institution, N.N. Burdenko National Medical Research Center of Neurosurgery, the Ministry of Health of the Russian Federation, 125047 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekaterina M.","family":"Merzlyak","sequence":"additional","affiliation":[{"name":"Shemyakin & Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"},{"name":"Institute of Translational Medicine, Pirogov Russian National Research Medical University, 117997 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga V.","family":"Britanova","sequence":"additional","affiliation":[{"name":"Shemyakin & Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"},{"name":"Institute of Translational Medicine, Pirogov Russian National Research Medical University, 117997 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandr M.","family":"Sapozhnikov","sequence":"additional","affiliation":[{"name":"Shemyakin & Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8119-8247","authenticated-orcid":false,"given":"Elena I.","family":"Kovalenko","sequence":"additional","affiliation":[{"name":"Shemyakin & Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Luo, Z., Li, Z., Martin, L., Hu, Z., Wu, H., Wan, Z., Kilby, M., Heath, S.L., Huang, L., and Jiang, W. 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