NK cells play a decisive role in controlling hCMV infection by combining innate and adaptive-like immune reactions. The hCMV-derived VMAPRTLFL (LFL) peptide is a potent activator of NKG2C+ NK cells. Proposed here is an autologous system of LFL stimulation without T lymphocytes and exogenous cytokines that allows us to evaluate NK-cell hCMV-specific responses in more native settings. In this model, we evaluated LFL-induced IFNγ production, focusing on signaling pathways and the degranulation and proliferation of NK cells orchestrated by microenvironment cytokine production and analyzed the transcriptome of expanded NK cells. NK cells of individuals having high anti-hCMV-IgG levels, in contrast to NK cells of hCMV-seronegative and low-positive donors, displayed increased IFNγ production and degranulation and activation levels and enhanced proliferation upon LFL stimulation. Cytokine profiles of these LFL-stimulated cultures demonstrated a proinflammatory shift. LFL-induced NK-cell IFNγ production was dependent on the PI3K and Ras/Raf/Mek signaling pathways, independently of cytokines. In hCMV-seropositive individuals, this model allowed obtaining NK-cell antigen-specific populations proliferating in response to LFL. The transcriptomic profile of these expanded NK cells showed increased adaptive gene expression and metabolic activation. The results complement the existing knowledge about hCMV-specific NK-cell response. This model may be further exploited for the identification and characterization of antigen-specific NK cells.

• Klíčová slova
• ERK1/2, HLA-E, IFNγ, NKG2C, RNAseq, cytokines, hCMV, memory NK cells,
• MeSH
• buňky NK MeSH
• cytokiny metabolismus   MeSH
• cytomegalovirové infekce * MeSH
• Cytomegalovirus MeSH
• lidé MeSH
• prezentace antigenu * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cytokiny MeSH

The interest in NK cells and their cytotoxic activity against tumour, infected or transformed cells continuously increases as they become a new efficient and off-the-shelf agents in immunotherapies. Their actions are balanced by a wide set of activating and inhibitory receptors, recognizing their complementary ligands on target cells. One of the most studied receptors is the activating CD94/NKG2C molecule, which is a member of the C-type lectin-like family. This review is intended to summarise latest research findings on the clinical relevance of NKG2C receptor and to examine its contribution to current and potential therapeutic strategies. It outlines functional characteristics and molecular features of CD94/NKG2C, its interactions with HLA-E molecule and presented antigens, pointing out a key role of this receptor in immunosurveillance, especially in the human cytomegalovirus infection. Additionally, the authors attempt to shed some light on receptor's unique interaction with its ligand which is shared with another receptor (CD94/NKG2A) with rather opposite properties.

• Klíčová slova
• HLA-E, NK cell receptors, NK cells, NKG2C,
• MeSH
• buňky NK MeSH
• lektinové receptory NK-buněk - podrodina C * MeSH
• lidé MeSH
• ligandy MeSH
• MHC antigeny I. třídy * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• lektinové receptory NK-buněk - podrodina C * MeSH
• ligandy MeSH
• MHC antigeny I. třídy * MeSH

The human cytomegalovirus (HCMV) is extremely prevalent in the human population. Infection by HCMV is life threatening in immune compromised individuals and in immune competent individuals it can cause severe birth defects, developmental retardation and is even associated with tumor development. While numerous mechanisms were developed by HCMV to interfere with immune cell activity, much less is known about cellular mechanisms that operate in response to HCMV infection. Here we demonstrate that in response to HCMV infection, the expression of the short form of the RNA editing enzyme ADAR1 (ADAR1-p110) is induced. We identified the specific promoter region responsible for this induction and we show that ADAR1-p110 can edit miR-376a. Accordingly, we demonstrate that the levels of the edited-miR-376a (miR-376a(e)) increase during HCMV infection. Importantly, we show that miR-376a(e) downregulates the immune modulating molecule HLA-E and that this consequently renders HCMV infected cells susceptible to elimination by NK cells.

• MeSH
• adenosindeaminasa genetika   MeSH
• buňky NK imunologie   MeSH
• cytomegalovirové infekce genetika   imunologie   MeSH
• Cytomegalovirus MeSH
• editace RNA genetika   MeSH
• lidé MeSH
• mikro RNA genetika   MeSH
• proteiny vázající RNA MeSH
• western blotting MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ADARB1 protein, human MeSH Prohlížeč
• adenosindeaminasa MeSH
• mikro RNA MeSH
• proteiny vázající RNA MeSH