NK cell education: Physiological and pathological influences

Rascle, Philippe; Woolley, Griffin; Jost, Stéphanie; Manickam, Cordelia; Reeves, R. Keith

doi:10.3389/fimmu.2023.1087155

Cited by 12 publications

(11 citation statements)

References 107 publications

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“…Here, we sought to evaluate whether the reovirus has developed mechanisms to impair NK cell cytotoxicity towards infected cells. We analyzed the levels of NKG2D ligands on the surface of reovirus-infected tumor cells, as NKG2D is a dominant NK cell receptor that augments NK-cell anti-viral activity ( 29 , 31 , 32 ). We infected the human melanoma cell line MNT-1, and human glioblastoma cell line U87-MG with reovirus T3D.…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Natural killer (NK) cells are innate lymphoid cells which are considered to be a key factor in the defense against tumor transformation and viral infections, as they can identify a wide range of patterns associated with “danger,” and unleash a cytotoxic response towards those patterns ( 29 ). NK cell cytotoxicity is regulated by an array of activating and inhibitory receptors ( 30 ), with the NKG2D receptor being among the most prominent activating receptors of NK cells ( 29 , 31 , 32 ). The NKG2D receptor binds to eight stress-induced ligands present on the cell surface, which are split into two families: the MHC class I chain-related protein (MIC) family, which includes MICA and MICB, and the UL16-binding protein (ULBP) family, which includes ULBP1-6.…”

Section: Introductionmentioning

confidence: 99%

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Reovirus infection of tumor cells reduces the expression of NKG2D ligands, leading to impaired NK-cell cytotoxicity and functionality

Khaleafi,

Zeleznjak,

Cordela

et al. 2023

Front. Immunol.

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In recent years, reoviruses have been of major interest in immunotherapy because of their oncolytic properties. Preclinical and clinical trials, in which reovirus was used for the treatment of melanoma and glioblastoma, have paved the way for future clinical use of reovirus. However, little is known about how reovirus infection affects the tumor microenvironment and immune response towards infected tumor cells. Studies have shown that reovirus can directly stimulate natural killer (NK) cells, but how reovirus affects cellular ligands on tumor cells, which are ultimately key to tumor recognition and elimination by NK cells, has not been investigated. We tested how reovirus infection affects the binding of the NK Group-2 member D (NKG2D) receptor, which is a dominant mediator of NK cell anti-tumor activity. Using models of human-derived melanoma and glioblastoma tumors, we demonstrated that NKG2D ligands are downregulated in tumor cells post-reovirus-infection due to the impaired translation of these ligands in reovirus-infected cells. Moreover, we showed that downregulation of NKG2D ligands significantly impaired the binding of NKG2D to infected tumor cells. We further demonstrated that reduced recognition of NKG2D ligands significantly alters NK cell anti-tumor cytotoxicity in human primary NK cells and in the NK cell line NK-92. Thus, this study provides novel insights into reovirus-host interactions and could lead to the development of novel reovirus-based therapeutics that enhance the anti-tumor immune response.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Reovirus infection of tumor cells reduces the expression of NKG2D ligands, leading to impaired NK-cell cytotoxicity and functionality

Khaleafi,

Zeleznjak,

Cordela

et al. 2023

Front. Immunol.

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“…dNKs, itself, has two KIR-binding epitopes of HLA-C: KIR2DL1 and KIR2DL3 [ 40 ]. This recognition of self-MHC class I (MHC-I) via inhibitory NK cell receptors is termed as NK cell education, which prevents NK cell auto-reactivity and maintains tolerance to itself [ 41 ]. But NK education does not exclusively rely on KIRs.…”

Section: Discussionmentioning

confidence: 99%

Single-cell characterization of self-renewing primary trophoblast organoids as modeling of EVT differentiation and interactions with decidual natural killer cells

Zhuang,

Cao,

et al. 2023

BMC Genomics

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Background Extravillous trophoblast cell (EVT) differentiation and its communication with maternal decidua especially the leading immune cell type natural killer (NK) cell are critical events for placentation. However, appropriate in vitro modelling system and regulatory programs of these two events are still lacking. Recent trophoblast organoid (TO) has advanced the molecular and mechanistic research in placentation. Here, we firstly generated the self-renewing TO from human placental villous and differentiated it into EVTs (EVT-TO) for investigating the differentiation events. We then co-cultured EVT-TO with freshly isolated decidual NKs for further study of cell communication. TO modelling of EVT differentiation as well as EVT interaction with dNK might cast new aspect for placentation research. Results Single-cell RNA sequencing (scRNA-seq) was applied for comprehensive characterization and molecular exploration of TOs modelling of EVT differentiation and interaction with dNKs. Multiple distinct trophoblast states and dNK subpopulations were identified, representing CTB, STB, EVT, dNK1/2/3 and dNKp. Lineage trajectory and Seurat mapping analysis identified the close resemblance of TO and EVT-TO with the human placenta characteristic. Transcription factors regulatory network analysis revealed the cell-type specific essential TFs for controlling EVT differentiation. CellphoneDB analysis predicted the ligand-receptor complexes in dNK-EVT-TO co-cultures, which relate to cytokines, immunomodulation and angiogenesis. EVT was known to affect the immune properties of dNK. Our study found out that on the other way around, dNKs could exert effects on EVT causing expression changes which are functionally important. Conclusion Our study documented a single-cell atlas for TO and its applications on EVT differentiation and communications with dNKs, and thus provide methodology and novel research cues for future study of human placentation.

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“…Unlike classical HLA-Ia, the HLA-Ib molecules have a limited number of polymorphisms and low expression on the cell surface [ 12 , 61 , 62 , 63 ]. They bind receptors expressed on T, NK and NK-like T lymphocytes.…”

Section: Non-classical Hla Class I Molecules (Hla-ib)mentioning

confidence: 99%

Non-Classical HLA Class 1b and Hepatocellular Carcinoma

Tornesello

Racanelli

et al. 2023

Biomedicines

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A number of studies are underway to gain a better understanding of the role of immunity in the pathogenesis of hepatocellular carcinoma and to identify subgroups of individuals who may benefit the most from systemic therapy according to the etiology of their tumor. Human leukocyte antigens play a key role in antigen presentation to T cells. This is fundamental to the host’s defense against pathogens and tumor cells. In addition, HLA-specific interactions with innate lymphoid cell receptors, such those present on natural killer cells and innate lymphoid cell type 2, have been shown to be important activators of immune function in the context of several liver diseases. More recent studies have highlighted the key role of members of the non-classical HLA-Ib and the transcript adjacent to the HLA-F locus, FAT10, in hepatocarcinoma. The present review analyzes the major contribution of these molecules to hepatic viral infection and hepatocellular prognosis. Particular attention has been paid to the association of natural killer and Vδ2 T-cell activation, mediated by specific HLA class Ib molecules, with risk assessment and novel treatment strategies to improve immunotherapy in HCC.

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NK cell education: Physiological and pathological influences

Cited by 12 publications

References 107 publications

Reovirus infection of tumor cells reduces the expression of NKG2D ligands, leading to impaired NK-cell cytotoxicity and functionality

Reovirus infection of tumor cells reduces the expression of NKG2D ligands, leading to impaired NK-cell cytotoxicity and functionality

Single-cell characterization of self-renewing primary trophoblast organoids as modeling of EVT differentiation and interactions with decidual natural killer cells

Non-Classical HLA Class 1b and Hepatocellular Carcinoma

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