HLA-DR Expression in Natural Killer Cells Marks Distinct Functional States, Depending on Cell Differentiation Stage.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Killer Cells, Natural*/metabolism ; Killer Cells, Natural*/immunology ; Cell Differentiation* ; HLA-DR Antigens*/metabolism ; HLA-DR Antigens*/genetics ; Interferon-gamma*/metabolism; Humans ; CD56 Antigen/metabolism ; Lymphocyte Activation/immunology ; Interleukin-2/metabolism ; Interleukin-2/pharmacology ; Cells, Cultured ; Nuclear Proteins ; Trans-Activators

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 IFNγ 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 ⁺ CD56 ^bright NK cells were characterized by a proliferative phenotype, while HLA-DR ⁺ CD56 ^dim 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 ^- 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 IFNγ. 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.

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22-15-00503 Russian Science Foundation

Keywords: CIITA; ERK1/2; HLA-DR; IFNg; IL-21; NK cells; RNAseq; STAT1; STAT3; metabolism

0 (HLA-DR Antigens)
82115-62-6 (Interferon-gamma)
0 (CD56 Antigen)
0 (MHC class II transactivator protein)
0 (Interleukin-2)
0 (Nuclear Proteins)
0 (Trans-Activators)

Date Created: 20240511 Date Completed: 20240511 Latest Revision: 20240513

20250114

PMC11083986

10.3390/ijms25094609

38731828