Structure of the human NK cell NKR-P1:LLT1 receptor:ligand complex reveals clustering in the immune synapse

Bláha, J.; Skálová, Tereza; Kalousková, Barbora; Skořepa, Ondřej; Cmunt, Denis; Grobárová, Valéria; Pažický, Samuel; Poláchová, Edita; Abreu, Celeste; Stránský, Jan; Kovaĺ, T.; Dušková, Jarmila; Zhao, Yuguang; Harlos, K.; Hašek, Jindřich; Dohnálek, Jan; Vaněk, Ondřej

doi:10.1038/s41467-022-32577-6

Cited by 10 publications

(4 citation statements)

References 84 publications

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“…On the other hand, transfection of LLT1 into NK target cells protects them from human NK cell cytotoxicity in a CD161-dependent manner ( 22 ), while NK cell treatment with soluble LLT1 protein leads to inhibition of NK cell cytotoxicity towards target cells, both in our study and recently published study of Blaha et al. ( 32 ). In agreement with other reports ( 21 ) indicating that CD161 expression on NK cells marks a pro-inflammatory NK cell subset, we observed that CD161 + NK cells more effectively limit SARS-CoV-2 infection.…”

Section: Discussionsupporting

confidence: 73%

SARS-CoV-2 infection impairs NK cell functions via activation of the LLT1-CD161 axis

et al. 2023

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IntroductionNatural killer (NK) cells plays a pivotal role in the control of viral infections, and their function depend on the balance between their activating and inhibitory receptors. The immune dysregulation observed in COVID-19 patients was previously associated with downregulation of NK cell numbers and function, yet the mechanism of inhibition of NK cell functions and the interplay between infected cells and NK cells remain largely unknown. MethodsIn this study we show that SARS-CoV-2 infection of airway epithelial cells can directly influence NK cell phenotype and functions in the infection microenvironment. NK cells were co-cultured with SARS-CoV-2 infected epithelial cells, in a direct contact with A549ACE2/TMPRSS2 cell line or in a microenvironment of the infection in a 3D ex vivo human airway epithelium (HAE) model and NK cell surface expression of a set of most important receptors (CD16, NKG2D, NKp46, DNAM-1, NKG2C, CD161, NKG2A, TIM-3, TIGIT, and PD-1) was analyzed. ResultsWe observed a selective, in both utilized experimental models, significant downregulation the proportion of CD161 (NKR-P1A or KLRB1) expressing NK cells, and its expression level, which was followed by a significant impairment of NK cells cytotoxicity level against K562 cells. What is more, we confirmed that SARS-CoV-2 infection upregulates the expression of the ligand for CD161 receptor, lectin-like transcript 1 (LLT1, CLEC2D or OCIL), on infected epithelial cells. LLT1 protein can be also detected not only in supernatants of SARS-CoV-2 infected A549ACE2/TMPRSS2 cells and HAE basolateral medium, but also in serum of COVID-19 patients. Finally, we proved that soluble LLT1 protein treatment of NK cells significantly reduces i) the proportion of CD161+ NK cells, ii) the ability of NK cells to control SARS-CoV-2 infection in A549ACE2/TMPRSS2 cells and iii) the production of granzyme B by NK cells and their cytotoxicity capacity, yet not degranulation level. ConclusionWe propose a novel mechanism of SARS-CoV-2 inhibition of NK cell functions via activation of the LLT1-CD161 axis.

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Section: Discussionsupporting

confidence: 73%

SARS-CoV-2 infection impairs NK cell functions via activation of the LLT1-CD161 axis

et al. 2023

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“…8c ). The genes of the C-type lectin superfamily are highly expressed in NK cells and may be involved in the regulation of the activity of NK cells 40 . The decreased activity of the CLEC pathway in LN + AM might result in a decrease in NK and NKT cells.…”

Section: Resultsmentioning

confidence: 99%

Delineating the early dissemination mechanisms of acral melanoma by integrating single-cell and spatial transcriptomic analyses

Wei,

Sun,

Shen

et al. 2023

Nat Commun

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Acral melanoma (AM) is a rare subtype of melanoma characterized by a high incidence of lymph node (LN) metastasis, a critical factor in tumor dissemination and therapeutic decision-making. Here, we employ single-cell and spatial transcriptomic analyses to investigate the dynamic evolution of early AM dissemination. Our findings reveal substantial inter- and intra-tumor heterogeneity in AM, alongside a highly immunosuppressive tumor microenvironment and complex intercellular communication networks, particularly in patients with LN metastasis. Notably, we identify a strong association between MYC+ Melanoma (MYC+MEL) and FGFBP2+NKT cells with LN metastasis. Furthermore, we demonstrate that LN metastasis requires a metabolic shift towards fatty acid oxidation (FAO) induced by MITF in MYC+MEL cells. Etomoxir, a clinically approved FAO inhibitor, can effectively suppress MITF-mediated LN metastasis. This comprehensive dataset enhances our understanding of LN metastasis in AM, and provides insights into the potential therapeutic targeting for the management of early AM dissemination.

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“…IFN-γ вырабатывают: естественные киллеры (NK), клетки естественных Т-киллеров, макрофаги, дендритные клетки (ДК), CD8 + и CD4 + T-клетки при адаптивном иммунном ответе и В-лимфоциты (таблица) [5][6][7][8][9][10][11][12][13][14][15][16][17][18].…”

Section: клетки-продуценты интерферона гаммаunclassified

Interferon gamma as a trigger of chronic viral infections and inflammatory dermatoses

Evdokimov,

Svechnikova,

Ponezheva

2024

Medicinskij sovet

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Interferon-gamma (IFN-γ) is the only representative of the type II interferon family regulating Th1 and Th2 immune responses. The discovery of IFN-γ is associated with the name of E. Frederick Wheelock. The expression of the IFNG gene provides a pleiotropic effect for IFN-γ, the main immune directions of this cytokine are antiviral, antibacterial and antiprotozoal. Unfortunately, in publications devoted to the relationship between the severity of inflammatory dermatoses (psoriasis, seborrheic dermatitis, atopic dermatitis) and levels of interferon gamma production, there is no consensus on the direct unity of these events. Although in most cases with acute viral diseases, an increase in interferon production is noted at the initial stages, but in some acute respiratory viral infections, its increase is not recorded (COVID-19, etc.), in cases of chronic viral diseases caused by retroviral infections – human immunodeficiency virus, human type 1 T-lymphotropic virus and endogenous human retroviruses as a result of prolonged exposure to IFN-γ on tissues, their damage may be noted, as well as a change in the functional state of CD4+ T cells. In cases of diseases caused by the herpes simplex virus 2, IFN-γ also has a complex effect on the intercellular relationships of infected and uninfected keratinocytes, as well as on the processes of apoptosis in Langerhans cells migrating to the dermis, which causes a violation of CD4+ and CD8+ involvement in the focus+ T-lymphocytes. In autoimmune diseases, IFN-γ can have a multidirectional effect. In particular, in patients with multiple sclerosis, IFN-γ regulates the processes of neuroinflammation and, depending on the concentration, can either reduce the number of CD11b+ myeloid cells of the central nervous system and reduce the infiltration of inflamed cells and normalize the processes of demyelination, or with an increase in IFN-γ production lead to reverse effects. At the same time, an enhancement of IFN-γ for transcription factors of differentially expressed genes in the case of systemic lupus erythematosus in patients has been proven.

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Structure of the human NK cell NKR-P1:LLT1 receptor:ligand complex reveals clustering in the immune synapse

Cited by 10 publications

References 84 publications

SARS-CoV-2 infection impairs NK cell functions via activation of the LLT1-CD161 axis

SARS-CoV-2 infection impairs NK cell functions via activation of the LLT1-CD161 axis

Delineating the early dissemination mechanisms of acral melanoma by integrating single-cell and spatial transcriptomic analyses

Interferon gamma as a trigger of chronic viral infections and inflammatory dermatoses

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