Galectin-9 Functionally Impairs Natural Killer Cells in Humans and Mice

Golden-Mason, Lucy; McMahan, Rachel H.; Strong, Michael; Reisdorph, Richard; Mahaffey, Spencer; Palmer, Brent E.; Cheng, Linling; Kulesza, Caroline; Hirashima, Mitsuomi; Niki, Toshiro; Rosen, Hugo R.

doi:10.1128/jvi.01085-12

Cited by 110 publications

(118 citation statements)

References 51 publications

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“…Interestingly, a recent report also indicates that hepatic NK cells from Gal-9-knockout mice produce significantly more IFN-␥ in response to murine cytomegalovirus (MCMV) infection than hepatic NK cells from wild-type mice, indicating the immunomodulatory potential of this molecule in the context of CMV infection (27). Future studies will examine the functional effects of HCMV-mediated Gal-9 upregulation on the antiviral immune response.…”

Section: Upregulation Of Galectin 9 By Hcmv Is Via Induction Of Intermentioning

confidence: 99%

Human Cytomegalovirus Upregulates Expression of the Lectin Galectin 9 via Induction of Beta Interferon

McSharry

Forbes

Cao

et al. 2014

J Virol

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Regulation of the lectin galectin 9 (Gal-9) was investigated for the first time during human cytomegalovirus (HCMV) infection. Gal-9 transcription was significantly upregulated in transplant recipients with reactivated HCMV in vivo. In vitro, Gal-9 was potently upregulated by HCMV independently of viral gene expression, with interferon beta (IFN-␤) identified as the mediator of this effect. This study defines an immunoregulatory protein potently increased by HCMV infection and a novel mechanism to control Gal-9 through IFN-␤ induction. P rimary human cytomegalovirus (HCMV) infection is followed by lifelong latency (1). Reactivation from latency is associated with severe morbidity and mortality in the immunocompromised, especially in the allogeneic hematopoietic stem cell transplant (HSCT) setting, where donor or recipient HCMV seropositivity is associated with adverse outcomes. In addition, HCMV is the leading infectious cause of birth defects in the developed world (2).Galectins are a family of lectins that preferentially bind ␤-galactosides. Galectin 9 (Gal-9) can modulate diverse biological activities, including cell adhesion, proliferation, apoptosis, and cell cycle progression (3). Despite such varied functions, regulation of Gal-9 is very poorly understood. Functionally, Gal-9 is best characterized as an immunoregulatory molecule controlling T-cell activity via interaction with its receptor, Tim-3 (4), although Tim-3-independent functions have also been described (5). Gal-9 can play an important role in virus life cycles. It modulates human immunodeficiency virus type 1 (HIV-1) entry (6, 7), while Gal-9-knockout mice exhibit more potent antiviral T-cell responses than wild-type mice (8, 9), and infection with Epstein-Barr virus (EBV) modulates Gal-9 expression to evade immune clearance, inducing apoptosis of EBV-specific CD4 ϩ T cells (10, 11). We investigated the expression of Gal-9 in the context of HCMV infection both in vivo and in vitro, identifying a novel, virally induced mechanism to promote Gal-9 expression.Galectin 9 is upregulated in hematopoietic stem cell transplant recipients with reactivated HCMV infection. We hypothesized that Gal-9 is upregulated in patients with active HCMV replication. Blood samples were drawn from HSCT recipients before peripheral blood mononuclear cells (PBMCs) were isolated by Ficoll density gradient centrifugation from patients with or without HCMV reactivation at a range of time points posttransplant (detailed in Tables 1 and 2). Patients were monitored for HCMV reactivation by quantitative PCR (qPCR; Roche Cobas Amplicor CMV Monitor test), with a sustained rise in serum HCMV genome copies above assay detection limits over at least two time points used to define HCMV reactivation.RNA was then isolated from PBMCs using an RNAqueous kit (Ambion). RNA was converted to cDNA using random primers and SuperScript III reverse transcriptase (Life Technologies). cDNA levels were assayed by qPCR (StepOnePlus real-time PCR system; Life Technologies) using 2ϫ Brilliant II SYBR g...

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Section: Upregulation Of Galectin 9 By Hcmv Is Via Induction Of Intermentioning

confidence: 99%

Human Cytomegalovirus Upregulates Expression of the Lectin Galectin 9 via Induction of Beta Interferon

McSharry

Forbes

Cao

et al. 2014

J Virol

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“…Clear causal relationships, however, remain elusive. The EBV-modified secreted exosomes containing galactin 1 and 9 have also been suggested to modulate NK cell control and could contribute to the virus' evasion of the innate immune system (Gandhi et al 2007;Klibi et al 2009;Golden-Mason et al 2013). More work and new models, as well as detailed and thorough investigation in patient samples, will be needed to understand and potentially exploit these natural protectors for patient treatment.…”

Section: Natural Killer Cellsmentioning

confidence: 98%

Innate Immune Recognition of EBV

Lünemann

Rowe

Nadal

2015

Epstein Barr Virus Volume 2

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The ability of Epstein-Barr virus (EBV) to establish latency despite specific immune responses and to successfully persist lifelong in the human host shows that EBV has developed powerful strategies and mechanisms to exploit, evade, abolish, or downsize otherwise effective immune responses to ensure its own survival. This chapter focuses on current knowledge on innate immune responses against EBV and its evasion strategies for own benefit and summarizes the questions that remain to be tackled. Innate immune reactions against EBV originate both from the main target cells of EBV and from nontarget cells, which are elements of the innate immune system. Thus, we structured our review accordingly but with a particular focus on the innate recognition of EBV in its two stages in its life cycle, latent state and lytic replication. Specifically, we discuss (I) innate sensing and resulting innate immune responses against EBV by its main target cells, focusing on (i) EBV transmission between epithelial cells and B cells and their life cycle stages; and (ii) elements of innate immunity in EBV's target cells. Further, we debate (II) the innate recognition and resulting innate immune responses against EBV by cells other than the main target cells, focusing on (iii) myeloid cells: dendritic cells, monocytes, macrophages, and neutrophil granulocytes; and (iv) natural killer cells. Finally, we address (III) how EBV counteracts or exploits innate immunity in its latent and lytic life cycle stages, concentrating on (v) TLRs; (vi) EBERs; and (vii) microRNAs.

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“…Further, KC-derived Gal-9 mediates T cell dysfunction and predicts poor prognosis in patients with hepatitis B-related hepatocellular carcinoma (95). Gal-9 has pleiotropic roles that include the inhibition and regulation of NK cell functions that may impact viral persistence (96).…”

Section: Figurementioning

confidence: 99%

Emerging concepts in immunity to hepatitis C virus infection

Rosen¹

2013

J. Clin. Invest.

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Since the discovery of hepatitis C virus (HCV) by molecular cloning almost a quarter of a century ago, unprecedented at the time because the virus had never been grown in cell culture or detected serologically, there have been impressive strides in many facets of our understanding of the natural history of the disease, the viral life cycle, the pathogenesis, and antiviral therapy. It is apparent that the virus has developed multiple strategies to evade immune surveillance and eradication. This Review covers what we currently understand of the temporal and spatial immunological changes within the human innate and adaptive host immune responses that ultimately determine the outcomes of HCV infection. Conflict of interest:The author has declared that no conflict of interest exists. Citation for this article:

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Galectin-9 Functionally Impairs Natural Killer Cells in Humans and Mice

Cited by 110 publications

References 51 publications

Human Cytomegalovirus Upregulates Expression of the Lectin Galectin 9 via Induction of Beta Interferon

Human Cytomegalovirus Upregulates Expression of the Lectin Galectin 9 via Induction of Beta Interferon

Innate Immune Recognition of EBV

Emerging concepts in immunity to hepatitis C virus infection

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