The decreased expression of Siglec-7 represents an early marker of dysfunctional natural killer–cell subsets associated with high levels of HIV-1 viremia

Brunetta, Enrico; Fogli, Manuela; Varchetta, Stefania; Bozzo, Luisa; Hudspeth, Kelly; Marcenaro, Emanuela; Moretta, Alessandro; Mavilio, Domenico

doi:10.1182/blood-2009-06-226332

Cited by 128 publications

(158 citation statements)

References 41 publications

(66 reference statements)

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“…It is likely that CD56 2 CD16 + cells arise from maturation of CD56 dim CD16 + NK cells. It will be of interest to determine whether CD56 + NK cells expressing low levels of FcRg, TCRz, and DAP12 represent a precursor stage toward losing CD56, similar to the reduction of SIGLEC-7 expression (33,34). Consistent with this concept, we have also observed a decreased expression of CD56 (data not shown) in addition to low CD16 expression within CD56 + NK cells from HIV-infected patients both on and off therapy.…”

Section: Discussionsupporting

confidence: 72%

Virologically Suppressed HIV Patients Show Activation of NK Cells and Persistent Innate Immune Activation

Lichtfuss

Cheng

Farsakoglu

et al. 2012

The Journal of Immunology

105

103

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FcRγ is an ITAM-containing adaptor required for CD16 signaling and function in NK cells. We have previously shown that NK cells from HIV patients receiving combination antiretroviral therapy (cART) have decreased FcRγ expression, but the factors causing this are unknown. We conducted a cross-sectional study of cART-naive viremic patients (ART−), virologically suppressed patients receiving cART (ART+), and HIV-uninfected controls. CD8+ T cells were activated, as assessed by CD38+HLA-DR+ expression, in ART− patients (p < 0.0001), which was significantly reduced in ART+ patients (p = 0.0005). In contrast, CD38+HLA-DR+ NK cells were elevated in ART− patients (p = 0.0001) but did not decrease in ART+ patients (p = 0.88). NK cells from both ART− and ART+ patients showed high levels of spontaneous degranulation in ex vivo whole blood assays as well as decreased CD16 expression (p = 0.0001 and p = 0.0025, respectively), FcRγ mRNA (p < 0.0001 for both groups), FcRγ protein expression (p = 0.0016 and p < 0.0001, respectively), and CD16-dependent Syk phosphorylation (p = 0.0001 and p = 0.003, respectively). HIV-infected subjects showed alterations in NK activation, degranulation, CD16 expression and signaling, and elevated plasma markers of inflammation and macrophage activation, that is, neopterin and sCD14, which remained elevated in ART+ patients. Alterations in NK cell measures did not correlate with viral load or CD4 counts. These data show that in HIV patients who achieve viral suppression following cART, NK cell activation persists. This suggests that NK cells respond to factors different from those driving T cell activation, but which are associated with inflammation in HIV patients.

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Section: Discussionsupporting

confidence: 72%

Virologically Suppressed HIV Patients Show Activation of NK Cells and Persistent Innate Immune Activation

Lichtfuss

Cheng

Farsakoglu

et al. 2012

The Journal of Immunology

105

103

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“…Thus, in such patients, we detected a rapid development of highly differentiated NKG2A 2 KIR + NKG2C + NK cells that, similar to what we observed in HIV/HCMV-infected subjects (19), were characterized by marked downregulation of Siglec-7 and, to a lower extent, of CD56. Notably, these NK cell populations, expressing a memory-like surface phenotype, could contribute to protection against leukemia relapse and to control of infections after transplantation (17,18,20).…”

supporting

confidence: 63%

“…So far, the HLA class I specificity of activating KIRs has been clearly demonstrated only for KIR2DS1 and KIR2DS4 (6)(7)(8). KIR genes are located on chromosome 19 and are inherited as haplotypes. Two basic KIR haplotypes can be found in the human genome: group A haplotypes, which have a fixed number of genes that encode inhibitory receptors (with the exception of the activating receptor KIR2DS4), and group B haplotypes, which have variable gene content, including additional activating KIR genes (4,9).…”

mentioning

confidence: 99%

Human Cytomegalovirus Infection Promotes Rapid Maturation of NK Cells Expressing Activating Killer Ig–like Receptor in Patients Transplanted with NKG2C−/− Umbilical Cord Blood

Chiesa

Falco

Bertaina

et al. 2014

The Journal of Immunology

Self Cite

145

112

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NK cells are the first lymphoid population recovering after allogeneic hematopoietic stem cell transplantation and play a crucial role in early immunity after the graft. Recently, it has been shown that human CMV (HCMV) infection/reactivation can deeply influence NK cell reconstitution after umbilical cord blood transplantation by accelerating the differentiation of mature NKG2A−killer Ig-like receptor (KIR)+ NK cells characterized by the expression of the NKG2C-activating receptor. In view of the hypothesis that NKG2C could be directly involved in NK cell maturation driven by HCMV infection, we analyzed the maturation and function of NK cells developing in three patients with hematological malignancies given umbilical cord blood transplantation from donors carrying a homozygous deletion of the NKG2C gene. We show that HCMV infection can drive rapid NK maturation, characterized by the expansion of CD56dimNKG2A−KIR+ cells, even in the absence of NKG2C expression. Interestingly, this expanded mature NK cell subset expressed surface-activating KIR that could trigger NK cell cytotoxicity, degranulation, and IFN-γ release. Given the absence of NKG2C, it is conceivable that activating KIRs may play a role in the HCMV-driven NK cell maturation and that NK cells expressing activating KIRs might contribute, at least in part, to the control of infections after transplantation.

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“…In this regard recent studies indicated that human cytomegalovirus (HCMV) infection leads to NK cell differentiation/ maturation and a reconfiguration in the NK cell receptor repertoire, including upregulation of the NKG2C activating receptor 43 and downregulation of the sialic acid-binding immunoglobulinlike lectin (Siglec) 7 (or p75/AIRM-1) inhibitory receptor. 42,[44][45][46] Thus we analyzed PD-1 1 and PD-1 2 donors to figure out whether the expression of PD-1 correlated with altered expression of these NK cell markers.…”

Section: Pd-1 Can Be Expressed By Nk Cells Of Hdsmentioning

confidence: 99%

“…47,48 These results suggested a possible association between PD-1 expression in NK cells and HCMV infection. 42,45,46,49 Thus, when possible, HCMV seropositivity was also analyzed. We found that all the PD-1 1 subjects were seropositive for HCMV (Fig 2, C).…”

Section: Pd-1 Can Be Expressed By Nk Cells Of Hdsmentioning

confidence: 99%

Identification of a subset of human natural killer cells expressing high levels of programmed death 1: A phenotypic and functional characterization

Pesce

Greppi

Tabellini

et al. 2017

Journal of Allergy and Clinical Immunology

Self Cite

364

372

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Background: Programmed death 1 (PD-1) is an immunologic checkpoint that limits immune responses by delivering potent inhibitory signals to T cells on interaction with specific ligands expressed on tumor/virus-infected cells, thus contributing to immune escape mechanisms. Therapeutic PD-1 blockade has been shown to mediate tumor eradication with impressive clinical results. Little is known about the expression/function of PD-1 on human natural killer (NK) cells. Objective: We sought to clarify whether human NK cells can express PD-1 and analyze their phenotypic/functional features. Methods: We performed multiparametric cytofluorimetric analysis of PD-1 1 NK cells and their functional characterization using degranulation, cytokine production, and proliferation assays. Results: We provide unequivocal evidence that PD-1 is highly expressed (PD-1 bright ) on an NK cell subset detectable in the peripheral blood of approximately one fourth of healthy subjects. These donors are always serologically positive for human cytomegalovirus. PD-1 is expressed by CD56 dim but not CD56 bright NK cells and is confined to fully mature NK cells characterized by the NKG2A 2 KIR 1 CD57 1 phenotype. Proportions of PD-1 bright NK cells were higher in the ascites of a cohort of patients with ovarian carcinoma, suggesting their

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The decreased expression of Siglec-7 represents an early marker of dysfunctional natural killer–cell subsets associated with high levels of HIV-1 viremia

Cited by 128 publications

References 41 publications

Virologically Suppressed HIV Patients Show Activation of NK Cells and Persistent Innate Immune Activation

Virologically Suppressed HIV Patients Show Activation of NK Cells and Persistent Innate Immune Activation

Human Cytomegalovirus Infection Promotes Rapid Maturation of NK Cells Expressing Activating Killer Ig–like Receptor in Patients Transplanted with NKG2C−/− Umbilical Cord Blood

Identification of a subset of human natural killer cells expressing high levels of programmed death 1: A phenotypic and functional characterization

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