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Depletion but Activation of CD56^dimCD16⁺ NK Cells in Acute Infection with Severe Fever with Thrombocytopenia Syndrome Virus.

ABSTRACT: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with high mortality (12%-30%). The mechanism by which the SFTS bunyavirus (SFTSV) causes severe illness remains unclear. To evaluate the phenotypic and functional characteristics of the NK cell subsets in SFTS patients, twenty-nine SFTS patients were sequentially sampled from admission until recovery. Phenotypic and functional characteristics of NK cell subsets in circulating blood were analysed via flow cytometry. Then, correlations between NK cell subset frequencies and the SFTS index (SFTSI) were evaluated in all SFTS patients (15 mild, 14 severe) upon admission. The frequencies of CD56^dimCD16⁺ NK cells were greatly decreased in early SFTSV infection and were negatively correlated with disease severity. Additionally, higher Ki-67 and granzyme B expression and relatively lower NKG2A expression in CD56^dimCD16⁺ NK cells were observed in acute infection. Moreover, the effector function of CD56^dim NK cells was increased in the acute phase compared with the recovery phase in nine severe SFTS patients. Additionally, interleukin (IL)-15, interferon (IFN)-α, IL-18 and IFN-γ secretion was markedly increased during early infection. Collectively, despite depletion of CD56^dimCD16⁺ NK cells, activation and functional enhancement of CD56^dimCD16⁺ NK cells were still observed, suggesting their involvement in defence against early SFTSV infection.

SUBMITTER: Li M

PROVIDER: S-EPMC7736421 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Natural killer (NK) cells are innate cytotoxic and immunoregulatory lymphocytes that have a central role in anti-tumor immunity and play a critical role in mediating cellular immunity in advanced cancer immunotherapies, such as dendritic cell (DC) vaccines. Our group recently tested a novel recombinant adenovirus-transduced autologous DC-based vaccine that simultaneously induces T cell responses against three melanoma-associated antigens for advanced melanoma patients. Here, we examine the impact of this vaccine as well as the subsequent systemic delivery of high-dose interferon-α2b (HDI) on the circulatory NK cell profile in melanoma patients. At baseline, patient NK cells, particularly those isolated from high-risk patients with no measurable disease, showed altered distribution of CD56dim CD16+ and CD56dim CD16- NK cell subsets, as well as elevated serum levels of immune suppressive MICA, TN5E/CD73 and tactile/CD96, and perforin. Surprisingly, patient NK cells displayed a higher level of activation than those from healthy donors as measured by elevated CD69, NKp44 and CCR7 levels, and enhanced K562 killing. Elevated cytolytic ability strongly correlated with increased representation of CD56dim CD16+ NK cells and amplified CD69 expression on CD56dim CD16+ NK cells. While intradermal DC immunizations did not significantly impact circulatory NK cell activation and distribution profiles, subsequent HDI injections enhanced CD56bright CD16- NK cell numbers when compared to patients that did not receive HDI. Phenotypic analysis of tumor-infiltrating NK cells showed that CD56dim CD16- NK cells are the dominant subset in melanoma tumors. NanoString transcriptomic analysis of melanomas resected at baseline indicated that there was a trend of increased CD56dim NK cell gene signature expression in patients with better clinical response. These data indicate that melanoma patient blood NK cells display elevated activation levels, that intra-dermal DC immunizations did not effectively promote systemic NK cell responses, that systemic HDI administration can modulate NK cell subset distributions and suggest that CD56dim CD16- NK cells are a unique non-cytolytic subset in melanoma patients that may associate with better patient outcome.

Project description:BackgroundSystemic lupus erythematosus (SLE) is characterized by loss of immune tolerance and imbalance of immune cell subsets. Natural killer (NK) cells contribute to regulate both the innate and adaptive immune response. In this study, we aimed to detect alterations of peripheral NK cells and explore intrinsic mechanisms involving in NK cell abnormality in SLE.MethodsBlood samples from healthy controls (HCs) and patients with SLE and rheumatoid arthritis (RA) were collected. The NK count, NK subsets (CD56bright, CD56dimCD57-, and CD56dimCD57+), phenotypes, and apoptosis were evaluated with flow cytometer. Mitochondrial reactive oxygen species (mtROS) and total ROS levels were detected with MitoSOX Red and DCFH-DA staining respectively. Published data (GSE63829 and GSE23695) from Gene Expression Omnibus (GEO) was analyzed by Gene Set Enrichment Analysis (GSEA).ResultsTotal peripheral NK count was down-regulated in untreated SLE patients in comparison to that in untreated RA patients and HCs. SLE patients exhibited a selective reduction in peripheral CD56dimCD57+ NK cell proportion, which was negatively associated with disease activity and positively correlated with levels of complement(C)3 and C4. Compared with HCs, peripheral CD56dimCD57+ NK cells from SLE patients exhibited altered phenotypes, increased endogenous apoptosis and higher levels of mtROS and ROS. In addition, when treated with hydrogen peroxide (H2O2), peripheral CD56dimCD57+ NK cell subset was more prone to undergo apoptosis than CD56dimCD57- NK cells. Furthermore, this NK cell subset from SLE patients exhibited impaired cytotoxicity in response to activated CD4+ T cells in vitro.ConclusionOur study demonstrated a selective loss of mature CD56dimCD57+ NK cell subset in SLE patients, which may caused by preferential apoptosis of this subset under increased oxidative stress in SLE. The attenuated in vitro cytotoxicity of CD56dimCD57+ NK cells may contribute to the impaired ability of eliminating pathogenic CD4+ T cells in SLE.

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Depletion but Activation of CD56^dimCD16⁺ NK Cells in Acute Infection with Severe Fever with Thrombocytopenia Syndrome Virus.

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Dataset Information

Depletion but Activation of CD56dimCD16+ NK Cells in Acute Infection with Severe Fever with Thrombocytopenia Syndrome Virus.

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OmicsDI is part of the ELIXIR infrastructure

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Depletion but Activation of CD56^dimCD16⁺ NK Cells in Acute Infection with Severe Fever with Thrombocytopenia Syndrome Virus.