HLA-DR-expressing NK cells: Effective killers suspected for antigen presentation

Abstract

HLA-DR-expressing cells comprise an intriguing group of NK cells, which combine phenotypic characteristics of both NK cells and dendritic cells. These cells can be found in humans and mice; they are present in blood and tissues in healthy conditions and can expand in a spectrum of pathologies. HLA-DR + NK cells are functionally active: they produce proinflammatory cytokines, degranulate, and easily proliferate in response to stimuli. Additionally, HLA-DR + NK cells seem able to take in and then present certain antigens to CD4 + and CD8 + T cells, inducing their activation and proliferation, which puts them closer to professional antigen-presenting cells. It appears that these NK cells should be considerable players of the innate immune system, both due to their functional activity and regulation of the innate and adaptive immune responses. In this review, for the first time, we provide a detailed description and analysis of the available data characterizing phenotypic, developmental, and functional features of the HLA-DR + NK cells in a healthy condition and a disease. K E Y W O R D S antigen presentation, HLA-DR + NK cells, IFN gamma, MHC class II, NK cell activation 1 INTRODUCTION Human natural killer (NK) cells are the essential agents of the innate immune system, capable of lysing target cells without specific immunization and of regulating immune response by cytokine secretion and cell-to-cell interactions. 1,2 They express an array of activating and inhibitory receptors, which allow them to recognize and efficiently eliminate infected or tumor cells. 3 Recent studies indicate that the repertoire of NK cell receptors demonstrates certain variability, responding to the pro-and anti-inflammatory environment or pathogen type, which enables NK cells to "switch" between different functional states and even acquire features of immunologic memory. 2 A number of surface markers and receptors may appear de novo or Abbreviations: APC, antigen-presenting cell; ART, antiretroviral therapy; CAR, chimeric antigen receptor; DC, dendritic cell; HCMV, human cytomegalovirus; HCV, hepatitis C virus; KIR, killer-cell immunoglobulin-like receptor; MS, multiple sclerosis; NKG2A, natural killer group protein 2 member A; NKG2C, natural killer group protein 2 member C; PBMC, peripheral blood mononuclear cells; SEB, staphylococcal enterotoxin B; SLE, systemic lupus erythematosus; TT, tetanus toxoid. increase the expression level when NK cells get activated in the functional or proliferative way: CD69, CD25, NKp44, CD16, and, among them, HLA-DR-a subtype of MHC class II (MHC II). 4-7 HLA-DR as an activation marker was firstly described for T cells responding to stimulation with various mitogens and antigens or activated in mixed lymphocytic reactions. 8-11 It was shown that HLA-DR appears on the surface of only part of the T lymphocytes and later than all other activation markers (CD69, CD25, CD71). 12 A similar increase in the HLA-DR expression level was detected on NK cells, which were cultivated in the presence of various stimuli o...

HLA-DR-Positive NK Cells Expand in Response to Mycobacterium Tuberculosis Antigens and Mediate Mycobacteria-Induced T Cell Activation

“…In this work, we have revealed that HLA-DR-positive cells are also expanded among CD56 bright CD3 − and CD56 + CD3 + subsets in the peripheral blood of the individuals primarily infected with lung tuberculosis ( Figure 1A ). Considering the reduced content of CD3 + CD56 − T cells and CD3 − CD56 − HLA-DR + cells observed by us in these patients, HLA-DR + NK cells, which often display activated phenotype and functions both in normal conditions and during pathology ( 36 ), may compensate for certain deficiencies of the adaptive anti-mycobacterial response.…”

Single-Cell Transcriptomics Reveals Peripheral Immune Responses in Anti-Synthetase Syndrome-Associated Interstitial Lung Disease

“…Fourth, GO analysis for NK cells showed the enrichment of antigen processing and presentation of peptide antigen via MHC II, which needs to be interpreted carefully. NK cells are not professional antigen-presenting cells (APCs), and they are important members of the innate immune system to directly eliminate virus-infected cells and tumor cells through their natural cytotoxic capacity without prior priming ( 44 ). Genes enriched for antigen processing and presentation mainly included human leukocyte antigen (HLA) -DPB1, HLA-DPA1, HLA-DQA1, HLA-DRB1, and HLA-DRB5, all these enriched genes are classical HLA II molecules.…”

“…Genes enriched for antigen processing and presentation mainly included human leukocyte antigen (HLA) -DPB1, HLA-DPA1, HLA-DQA1, HLA-DRB1, and HLA-DRB5, all these enriched genes are classical HLA II molecules. HLA-DR-expressing NK cells have been reported to be detected in the blood and tissues in healthy individuals, and their functions are associated with enhanced production of proinflammatory cytokines, degranulation, and proliferation upon stimuli ( 44 ). In vitro , HLA-DR-expressing NK cells pre-activated with cytokines have been reported to induce nonspecific activation and partial differentiation of CD4 T cells in previous publications ( 45 , 46 ).…”

Immunophenotyping of Peripheral Blood Mononuclear Cells in Septic Shock Patients With High-Dimensional Flow Cytometry Analysis Reveals Two Subgroups With Differential Responses to Immunostimulant Drugs

“…In particular, we observed an increase of HLA-DR expression on NK cells in the Hyper subgroup as compared to the Hypo subgroup. HLA-DR + NK cells have been associated with a less mature phenotype with antigen-presentation ability (41,42). This might explain the overall hyper-responsiveness as seen in the Hyper subgroup where NKs, in addition to professional antigenpresenting cells such as DCs, leads to further activation of Tcells.…”