Search

Summary: Natural killer (NK) cells play a crucial role in controlling viral infections. The ability to kill infected cells without prior immunization, yet being tolerant to self, healthy cells, depends on the balance of germ-line encoded surface receptors. NK-cell receptors are divided into either activating, leading to activation of NK cell and its cytotoxic and pro-inflammatory activity, or inhibitory, providing tolerance for a target cell. The signals from inhibitory receptors dominate and NK-cell activation requires stimulation of activating receptors. In viral infections, NK-cell interaction with infected cells can result in activation, memory-like NK-cell differentiation, or NK-cell exhaustion, which constitutes one of the viral immune evasion mechanisms. All of these states are associated with the modulation of NK-cell receptor expression. In this review, we summarize the current knowledge of NK-cell receptors and their role in viral infection control, as well as the alterations of their expression observed in acute or chronic infections. We present recently discovered SARS-CoV-2-mediated modulation of NK-cell receptor expression and compare them with other human viral infections. Finally, since modulation of NK-cell receptor activation gives a promising addition to currently used antiviral therapies, we briefly discuss the clinical significance and future perspective of the application of agonists or antagonists of activating and inhibitory receptors, respectively. In sum, our review shows that although much is known about NK-cell receptor biology, a deeper understanding of NK-cell receptors role in viral infections is still needed. This review summarizes recent knowledge on NK cell receptor alterations mediated by viral infections, along with the mechanisms responsible for this modulation. We present recently discovered SARS-CoV-2-mediated modulation of NK cell receptor expression and compare them with other human viral infections. Graphical Abstract [ABSTRACT FROM AUTHOR]

Severe and/or recurrent infection with Herpes simplex virus (HSV) is observed in a large group of patients treated in clinical immunology facilities. Atypical and prolonged HSV infection is the most common clinical manifestation of disturbed NK cell development and functions, yet the molecular basis of these disorders is still largely unknown. Since recent findings indicated the importance of miRNA in regulating NK cell development, maturation and functions, the aim of our study was to investigate miRNA expression pattern in NK cells in patients with severe and/or recurrent infections with HSV and analyze the role of these miRNAs in NK cell antiviral response. As a result, miRNA expression pattern analysis of human best known 754 miRNAs revealed that patients with severe and/or recurrent HSV infection had substantially upregulated expression of four miRNAs: miR-27b, miR-199b, miR-369-3p and miR-491-3p, when compared to healthy controls. Selective inhibition of miR-27b, miR-199b, miR-369-3p and miR-491-3p expression in NK-92 cells resulted in profound upregulation of 4 genes (APOBEC3G, MAP2K3, MAVS and TLR7) and downregulation of 36 genes taking part in antiviral response or associated with signaling pathways of Toll-like receptors (TLR), NOD-like receptors, the retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) and type I IFN-related response. Additionally, flow cytometry analysis revealed that miR-369-3p and miR-491-3p inhibitors downregulated NK cell intracellular perforin expression, while the expression of granzyme B and IFNγ remained unchanged. Taken together, our study suggests a novel mechanism which may promote recurrence and severity of HSV infection, based on miRNAs-dependent posttranscriptional regulation of genes taking part in antiviral response of human NK cells. [ABSTRACT FROM AUTHOR]

Invariant natural killer T (iNKT) cells are a small population of thymus-derived T cells that are restricted by non-classical MHC class I molecule CD1d and express an evolutionary conserved TCR with an invariant α-chain. The frequency of iNKT cells in peripheral blood is very low, thus, accurate methods to identify and enumerate iNKT cells are needed. The aim of the study was to compare 6B11 mAb or α-GalCer-loaded CD1d dextramers usage in iNKT cell detection. The frequency of CD3 + CD56 + lymphocytes is much higher, with statistical significance ( p < 0,001), than real iNKT cells detected by 6B11 mAb or α-GalCer-loaded CD1d dextramers. The frequency of iNKT cells, recognized by 6B11 mAb or α-GalCer-loaded CD1d dextramers, was in a similar range. Nonetheless, when we compared whether 6B11 + and α-GalCer-loaded CD1d dextramers + are the same populations, it turned out that by this approach we were able to identify three distinct subsets of iNKT cells: i) 6B11 + /α-GalCer-loaded dextramer − cells, ii) 6B11 + /α-GalCer-loaded dextramer + cells, and iii) 6B11 − /α-GalCer-loaded dextramer + . Thus, although 6B11 mAb and α-GalCer-loaded dextramers may identify not exactly the same cells, application of these methods seems to give similar results of iNKT cell frequency in peripheral blood. It seems that both approaches for iNKT detection can be used for precise identification of these cells. Moreover, our results indicate that CD3 + CD56 + lymphocytes are a heterogeneous population of T cells, expressing activation markers of both NK and T lymphocytes, yet with not well characterized properties. [ABSTRACT FROM AUTHOR]

• NK cells expressing activating receptors (CD16, NKp46, NKp80, NKG2D and 2B4) and/or expression of these receptors was selectively downregulated in children with severe and/or recurrent HSV infection; • NTB-A receptor expression was upregulated on patients' CD16dimCD56bright NK cells and CD8+ T cell subsets; • HSV patients had increased percentage of CD4+ T cells expressing PD-1; • Two possible mechanisms promoting HSV infection - selective inhibition of activating receptors on NK cells, but not T cells, and upregulation of PD-1 on CD4+ T cells. Severe, recurrent or atypical Herpes simplex virus (HSV) infections are still posing clinical and diagnostic problem in clinical immunology facilities. However, the molecular background of this disorder is still unclear. The aim of this study was to investigate the expression of activating receptors on NK cells (CD16, NKp46, NKG2D, NKp80, 2B4, CD48 and NTB-A) and checkpoint molecule PD-1 on T lymphocytes and NK cells, in patients with severe and/or recurrent infections with HSV and age-matched healthy control subjects. As a result, we noticed that patients with severe and/or recurrent infection with HSV had significantly lower percentage of CD16brightCD56dim and higher percentage of CD16dimCD56bright NK cell subsets, when compared to control subjects, which may be associated with abnormal NK cell maturation during chronic HSV infection. Patients had also significantly downregulated expression of CD16 receptor on CD16bright NK cells. The expression of activating receptors was significantly reduced on patients' NK cells - either both the percentage of NK cells expressing the receptor and MFI of its expression (NKp46, NKp80 and 2B4 on CD16brightCD56dim cells and NKp46 on CD16dimCD56bright cells) or only MFI (NKG2D on both NK cell subsets). It should be noted that the reduction of receptor expression was limited to NK cells, since there was no differences in the percentage of receptor-positive cells or MFI on T cells. However, NTB-A receptor was the only one which expression was not only simultaneously changed in patients' NK and T cells, but also significantly upregulated on CD16dimCD56bright NK cell and CD8+ cell subsets. Patients had also upregulated proportion of CD4+ T cells expressing PD-1. Thus, we suggest that an increased percentage of PD-1+ cells may represent an independent indirect mechanism of downregulation of antiviral response, separate from the reduction of NK cell activating receptors expression. Altogether, our studies indicate two possible mechanisms which may promote perpetuation of HSV infection: 1) selective inhibition of activating receptors on NK cells, but not on T cells, and 2) upregulation of checkpoint molecule PD-1 on CD4+ T cells. [ABSTRACT FROM AUTHOR]