Siglec‐7 Defines a Highly Functional Natural Killer Cell Subset and Inhibits Cell‐Mediated Activities

Shao, Jianying; Yin, Wenwei; Zhang, Qiong‐Fang; Liu, Qian; Peng, Mingli; Hu, Huaidong; Hu, Ping; Ren, Hong; Zhang, Da‐Zhi

doi:10.1111/sji.12455

Cited by 53 publications

(56 citation statements)

References 55 publications

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“…FAS (CD95), which plays a central role in the physiologic regulation of programmed cell death and is up‐regulated on NK cells in response to cytokines, was down‐regulated at W8 on total and effector NKs. Siglec‐7, an NK cell inhibitory receptor, was up‐regulated on these populations at the same time (Fig. ).…”

Section: Resultsmentioning

confidence: 99%

“…The changes in NK phenotype that we observed late (predominantly 12 weeks after the end of treatment), comprising decreased expression of activation (CD69, CD161) and cytotoxicity (NKp30, NKp46, and TRAIL) receptors, suggest that the chronically activated NK phenotype characteristic of chronic HCV is reversed by ledipasvir/sofosbuvir therapy but that normalization of the activation status takes several weeks after the disappearance of virus. The expression patterns of FAS (CD95) and Siglec‐7 (CD328), which are altered at intermediate time points (W4‐W12), suggest that down‐regulation of the activation status of NK cells is a gradual process …”

Section: Discussionmentioning

confidence: 99%

“…The expression patterns of FAS (CD95) and Siglec-7 (CD328), which are altered at intermediate time points (W4-W12), suggest that down-regulation of the activation status of NK cells is a gradual process. (29,30) Data on NK cell dysfunction in the setting of chronic HCV favor a polarization model with overactive cytotoxic and inadequate IFN-c responses. (23,(37)(38)(39) Successful antiviral therapy, including DAAs, may result in normalization of NK cell function.…”

Section: Discussionmentioning

confidence: 99%

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Early and late changes in natural killer cells in response to ledipasvir/sofosbuvir treatment

Golden–Mason¹,

McMahan²,

Kriss³

et al. 2018

Hepatology Communications

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Chronic hepatitis C virus (HCV) infection is characterized by dysregulated natural killer (NK) cell responses. NKs play a critical role in achieving sustained responses to interferon (IFN)‐α‐based therapy. Rapid sustained HCV‐RNA clearance is now achieved with direct‐acting antivirals (DAAs). Studies of patients receiving first‐wave DAAs suggest NK functional restoration. Here, we investigate the effect of mainstream DAA treatment on NKs. We collected a prospective cohort of male HCV genotype 1‐infected patients treated with ledipasvir/sofosbuvir (n = 22). Peripheral blood was obtained at treatment start, week 2 (W2), W4, W8, and W12 of treatment and 12 weeks posttreatment. Flow cytometry was used to characterize NK responses to therapy. Mean baseline viral load was 1.75 million IU/mL. All subjects rapidly cleared virus and remained HCV RNA‐negative posttreatment. No change was seen in total NK levels; however, the frequency of immature NKs (clusters of differentiation [CD]56bright) decreased by W2 and was maintained throughout the study. Phenotypic changes were evident by W2/W4, coincident with rapid viral clearance. At W2, T‐cell immunoglobulin and mucin‐domain containing‐3 and CD161 were significantly increased, returning to pretreatment levels by W12. Some changes were not evident until late (W12 or posttreatment). Down‐regulation of several activation markers, including NKp30 and tumor necrosis factor–related apoptosis‐inducing ligand, was observed at W12 and sustained posttreatment. No difference was observed in IFN‐γ production or cytokine‐mediated killing of NK‐sensitive cell line K562 posttreatment compared to pretreatment. Conclusion: Our phenotype data suggest transient activation followed by dampening of NK cell activity to pretreatment levels. The NK response to ledipasvir/sofosbuvir is not universal in a homogeneous patient cohort. More studies are needed to elucidate the roles of NK cells in IFN‐free regimens, which will have implications for protection from re‐infection and fibrosis progression. (Hepatology Communications 2018;2:364‐375)

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Early and late changes in natural killer cells in response to ledipasvir/sofosbuvir treatment

Golden–Mason¹,

McMahan²,

Kriss³

et al. 2018

Hepatology Communications

View full text Add to dashboard Cite

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“…Siglec-7 is a sialic acid-binding protein that has an immune tyrosine-based inhibition motif (ITIM). Siglec-7 is expressed on highly active NK cells (56), and loss of expression is believed to correspond to dysfunction of NK cells, which occurs in chronic HIV and HCV infection (46,57). CD11b is a marker of maturation of NK cells in humans and mice (58,59).…”

Section: Discussionmentioning

confidence: 99%

Identification of NK Cell Subpopulations That Differentiate HIV-Infected Subject Cohorts with Diverse Levels of Virus Control

Pohlmeyer

Gonzalez

Irrinki

et al. 2019

J Virol

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HIV infection is controlled immunologically in a small subset of infected individuals without antiretroviral therapy (ART), though the mechanism of control is unclear. CD8 ϩ T cells are a critical component of HIV control in many immunological controllers. NK cells are also believed to have a role in controlling HIV infection, though their role is less well characterized. We used mass cytometry to simultaneously measure the levels of expression of 24 surface markers on peripheral NK cells from HIV-infected subjects with various degrees of HIV natural control; we then used machine learning to identify NK cell subpopulations that differentiate HIV controllers from noncontrollers. Using CITRUS (cluster identification, characterization, and regression), we identified 3 NK cell subpopulations that differentiated subjects with chronic HIV viremia (viremic noncontrollers [VNC]) from individuals with undetectable HIV viremia without ART (elite controllers [EC]). In a parallel approach, we identified 11 NK cell subpopulations that differentiated HIV-infected subject groups using k-means clustering after dimensionality reduction by t-neighbor stochastic neighbor embedding (tSNE) or linear discriminant analysis (LDA). Among these additional 11 subpopulations, the frequencies of 5 correlated with HIV DNA levels; importantly, significance was retained in 2 subpopulations in analyses that included only cohorts without detectable viremia. By comparing the surface marker expression patterns of all identified subpopulations, we revealed that the CD11b ϩ CD57 Ϫ CD161 ϩ Siglec-7 ϩ subpopulation of CD56 dim CD16 ϩ NK cells are more abundant in EC and HIV-negative controls than in VNC and that the frequency of these cells correlated with HIV DNA levels. We hypothesize that this population may have a role in immunological control of HIV infection. IMPORTANCE HIV infection results in the establishment of a stable reservoir of latently infected cells; ART is usually required to keep viral replication under control and disease progression at bay, though a small subset of HIV-infected subjects can control HIV infection without ART through immunological mechanisms. In this study, we sought to identify subpopulations of NK cells that may be involved in the natural immunological control of HIV infection. We used mass cytometry to measure surface marker expression on peripheral NK cells. Using two distinct semisupervised machine learning approaches, we identified a CD11b ϩ CD57 Ϫ CD161 ϩ Siglec-7 ϩ subpopulation of CD56 dim CD16 ϩ NK cells that differentiates HIV controllers from noncontrollers. These cells can be sorted out for future functional studies to assess their potential role in the immunological control of HIV infection.

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“…Although Siglec-7 is an iNKRs containing ITIM-like domains in its cytosolic tail, it has been also reported that Siglec-7 pos NK cells are more functionally relevant compared to their Siglec-7 neg counterparts. Indeed, the expression of Siglec-7 in NK cells is associated with higher levels of aNKRs (i.e., CD16, NKp30, NKp46) and lower levels of iNKRs (i.e., CD94/NKG2A, CD158b) (76). This likely explains the fact that NK cells still retain a certain degree of antiviral and antitumor functions in the acute phases of HIV-1 infection, while become anergic and highly dysfunctional only in the chronic stages of the disease featuring the expansion of the Siglec-7 neg /CD56 neg NK cells (56).…”

Section: Kinetics Of Siglecs During the Course Of Hiv-1 Infectionmentioning

confidence: 99%

Host Immune Responses in HIV-1 Infection: The Emerging Pathogenic Role of Siglecs and Their Clinical Correlates

et al. 2017

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A better understanding of the mechanisms employed by HIV-1 to escape immune responses still represents one of the major tasks required for the development of novel therapeutic approaches targeting a disease still lacking a definitive cure. Host innate immune responses against HIV-1 are key in the early phases of the infection as they could prevent the development and the establishment of two hallmarks of the infection: chronic inflammation and viral reservoirs. Sialic acid-binding immunoglobulin-like lectins (Siglecs) belong to a family of transmembrane proteins able to dampen host immune responses and set appropriate immune activation thresholds upon ligation with their natural ligands, the sialylated carbohydrates. This immune-modulatory function is also targeted by many pathogens that have evolved to express sialic acids on their surface in order to escape host immune responses. HIV-1 envelope glycoprotein 120 (gp120) is extensively covered by carbohydrates playing active roles in life cycle of the virus. Indeed, besides forming a protecting shield from antibody recognition, this coat of N-linked glycans interferes with the folding of viral glycoproteins and enhances virus infectivity. In particular, the sialic acid residues present on gp120 can bind Siglec-7 on natural killer and monocytes/macrophages and Siglec-1 on monocytes/macrophages and dendritic cells. The interactions between these two members of the Siglec family and the sialylated glycans present on HIV-1 envelope either induce or increase HIV-1 entry in conventional and unconventional target cells, thus contributing to viral dissemination and disease progression. In this review, we address the impact of Siglecs in the pathogenesis of HIV-1 infection and discuss how they could be employed as clinic and therapeutic targets.

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Siglec‐7 Defines a Highly Functional Natural Killer Cell Subset and Inhibits Cell‐Mediated Activities

Cited by 53 publications

References 55 publications

Early and late changes in natural killer cells in response to ledipasvir/sofosbuvir treatment

Early and late changes in natural killer cells in response to ledipasvir/sofosbuvir treatment

Identification of NK Cell Subpopulations That Differentiate HIV-Infected Subject Cohorts with Diverse Levels of Virus Control

Host Immune Responses in HIV-1 Infection: The Emerging Pathogenic Role of Siglecs and Their Clinical Correlates

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