Selective downregulation of natural killer activating receptors on NK cells and upregulation of PD-1 expression on T cells in children with severe and/or recurrent Herpes simplex virus infections

Lenart, Marzena; Kluczewska, Anna; Szaflarska, Anna; Rutkowska-Zapała, Magdalena; Wąsik, Magdalena; Ziemiańska-Pięta, Anna; Kobylarz, Krzysztof; Pituch‐Noworolska, Anna; Siedlar, Maciej

doi:10.1016/j.imbio.2021.152097

Cited by 8 publications

(5 citation statements)

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“…However, in reactive processes we observed lower NKp80 levels, in addition to lower positivity for CD56, in reactive vs normal blood NK-cells. This finding might be due to downregulation of NKp80 expression during NK-cell activation ( 53 ), as also demonstrated here via short-term in vitro stimulation assays. This reinforces the need of CD16 in addition to NKp80, for a more accurate identification of normal and reactive NK-cells.…”

Section: Discussionsupporting

confidence: 76%

A novel NKp80-based strategy for universal identification of normal, reactive and tumor/clonal natural killer-cells in blood

Morán-Plata,

Muñoz-García,

González-González

et al. 2024

Front. Immunol.

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PurposeNatural killer (NK) cells are traditionally identified by flow cytometry using a combination of markers (CD16/CD56/CD3), because a specific NK-cell marker is still missing. Here we investigated the utility of CD314, CD335 and NKp80, compared to CD16/CD56/CD3, for more robust identification of NK-cells in human blood, for diagnostic purposes.MethodsA total of 156 peripheral blood (PB) samples collected from healthy donors (HD) and patients with diseases frequently associated with loss/downregulation of classical NK-cell markers were immunophenotyped following EuroFlow protocols, aimed at comparing the staining profile of total blood NK-cells for CD314, CD335 and NKp80, and the performance of distinct marker combinations for their accurate identification.ResultsNKp80 showed a superior performance (vs. CD314 and CD335) for the identification of NK-cells in HD blood. Besides, NKp80 improved the conventional CD16/CD56/CD3-based strategy to identify PB NK-cells in HD and reactive processes, particularly when combined with CD16 for further accurate NK-cell-subsetting. Although NKp80+CD16 improved the identification of clonal/tumor NK-cells, particularly among CD56- cases (53%), aberrant downregulation of NKp80 was observed in 25% of patients, in whom CD56 was useful as a complementary NK-cell marker. As NKp80 is also expressed on T-cells, we noted increased numbers of NKp80+ cytotoxic T-cells at the more advanced maturation stages, mostly in adults.ConclusionHere we propose a new robust approach for the identification of PB NK-cells, based on the combination of NKp80 plus CD16. However, in chronic lymphoproliferative disorders of NK-cells, addition of CD56 is recommended to identify clonal NK-cells, due to their frequent aberrant NKp80- phenotype.

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Section: Discussionsupporting

confidence: 76%

A novel NKp80-based strategy for universal identification of normal, reactive and tumor/clonal natural killer-cells in blood

Morán-Plata,

Muñoz-García,

González-González

et al. 2024

Front. Immunol.

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“…In summary, not only did we find that a different distribution of NK cell subsets in COVID-19 patients could lead to an impaired innate cellular barrier, but we also found that a higher frequency of inhibitory KIR receptors could enhance the impairment of these cells. Another mechanism that can suppress NK cell antiviral activity is the elevated IL-6 and IL-10 levels in COVID-19 through the down-modulation of the activating receptor NKG2D [40,41]. Importantly, this impaired NK cell cytotoxicity is partially recovered earlier after infection.…”

Section: Discussionmentioning

confidence: 99%

Expansion of CD56dimCD16neg NK Cell Subset and Increased Inhibitory KIRs in Hospitalized COVID-19 Patients

Casado

Moraga

Vizcarra

et al. 2021

Viruses

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Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) infection induces elevated levels of inflammatory cytokines, which are mainly produced by the innate response to the virus. The role of NK cells, which are potent producers of IFN-γ and cytotoxicity, has not been sufficiently studied in the setting of SARS-CoV-2 infection. We confirmed a different distribution of NK cell subsets in hospitalized COVID-19 patients despite their NK cell deficiency. The impairment of this innate defense is mainly focused on the cytotoxic capacity of the CD56dim NK cells. On the one hand, we found an expansion of the CD56dimCD16neg NK subset, lower cytotoxic capacities, and high frequencies of inhibitory 2DL1 and 2DL1/S1 KIR receptors in COVID-19 patients. On the other hand, the depletion of CD56dimCD16dim/bright NK cell subsets, high cytotoxic capacities, and high frequencies of inhibitory 2DL1 KIR receptors were found in COVID-19 patients. In contrast, no differences in the distribution of CD56bright NK cell subsets were found in this study. These alterations in the distribution and phenotype of NK cells might enhance the impairment of this crucial innate line of defense during COVID-19 infection.

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“…mCD48 levels in COVID-19 patients might be elevated due to the concomitant increased levels of INFγ (Akbari et al, 2020), known to upregulate CD48 expression, or due to other still undiscovered factors. Notably, virus infections seem to influence expression levels of mCD48 as on B-cells obtained from mononucleosis patients mCD48 is elevated (Thorley-Lawson et al, 1982), while on peripheral blood CD4+ T cells from T-lymphotropic virus 1 (HTLV-1) infected patients it is decreased (Ezinne et al, 2014), and on NK-cells of herpes simplex virus (HSV) infected patients it remains stable (Lenart et al, 2021). Furthermore, mCD48 expression is reported to be elevated in CD4+ T-cells infected in vitro with the human immunodeficiency virus (HIV) (Tremblay-McLean et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

COVID-19 patients have increased levels of membrane-associated and soluble CD48

Pahima

Zaffran

Ben‐Chetrit

et al. 2022

Preprint

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COVID-19 is a respiratory-centered systemic disorder caused by SARS-CoV-2. The disease can progress into a severe form causing acute lung injury. CD48 is a co-signaling receptor, existing as both membrane-bound and soluble forms reported to be dysregulated in several inflammatory conditions. Therefore, we reasoned that CD48 could be deregulated in COVID-19 as well. Here we analyzed CD48 expression in autoptic sections and peripheral blood leukocytes and sera of COVID-19 patients by gene expression profiling (HTG autoimmune panel), immunohistochemistry, flow cytometry and ELISA. Lung tissue of COVID-19 patients showed increased CD48 mRNA expression and infiltration of CD48+ lymphocytes. In the peripheral blood, mCD48 was considerably increased on all evaluated cells, and additionally, sCD48 levels were significantly higher in COVID-19 patients independently of disease severity. Considering the alterations of mCD48 and sCD48, a specific role for CD48 in COVID-19 can be assumed, suggesting it as a potential target for therapy.

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Selective downregulation of natural killer activating receptors on NK cells and upregulation of PD-1 expression on T cells in children with severe and/or recurrent Herpes simplex virus infections

Cited by 8 publications

References 65 publications

A novel NKp80-based strategy for universal identification of normal, reactive and tumor/clonal natural killer-cells in blood

A novel NKp80-based strategy for universal identification of normal, reactive and tumor/clonal natural killer-cells in blood

Expansion of CD56dimCD16neg NK Cell Subset and Increased Inhibitory KIRs in Hospitalized COVID-19 Patients

COVID-19 patients have increased levels of membrane-associated and soluble CD48

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