Chlamydia psittaci-Infected Dendritic Cells Communicate with NK Cells via Exosomes To Activate Antibacterial Immunity

ABSTRACT Dendritic cells (DCs) and natural killer (NK) cells are critically involved in the early response against various bacterial microbes. Functional activation of infected DCs and NK cell-mediated gamma interferon (IFN-γ) secretion essentially contribute to the protective immunity against Chlamydia. How DCs and NK cells cooperate during the antichlamydial response is not fully understood. Therefore, in the present study, we investigated the functional interplay between Chlamydia-infected DCs and NK cells. Our biochemical and cell biological experiments show that Chlamydia psittaci-infected DCs display enhanced exosome release. We find that such extracellular vesicles (referred to as dexosomes) do not contain infectious bacterial material but strongly induce IFN-γ production by NK cells. This directly affects C. psittaci growth in infected target cells. Furthermore, NK cell-released IFN-γ in cooperation with tumor necrosis factor alpha (TNF-α) and/or dexosomes augments apoptosis of both noninfected and infected epithelial cells. Thus, the combined effect of dexosomes and proinflammatory cytokines restricts C. psittaci growth and attenuates bacterial subversion of apoptotic host cell death. In conclusion, this provides new insights into the functional cooperation between DCs, dexosomes, and NK cells in the early steps of antichlamydial defense.

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Downmodulation of Effector Functions in NK Cells upon Toxoplasma gondii Infection

Infection and Immunity ◽

10.1128/iai.00069-17 ◽

2017 ◽

Vol 85 (10) ◽

Cited By ~ 7

Author(s):

M. Afifa Sultana ◽

Ann Du ◽

Berit Carow ◽

Catrine M. Angbjär ◽

Jessica M. Weidner ◽

...

Keyword(s):

Toxoplasma Gondii ◽

Nk Cells ◽

Transforming Growth Factor ◽

Nk Cell ◽

Target Cells ◽

Immune Recognition ◽

Content Type ◽

Cell Functions ◽

Ifn Γ

ABSTRACT The obligate intracellular parasite Toxoplasma gondii can actively infect any nucleated cell type, including cells from the immune system. The rapid transfer of T. gondii from infected dendritic cells to effector natural killer (NK) cells may contribute to the parasite's sequestration and shielding from immune recognition shortly after infection. However, subversion of NK cell functions, such as cytotoxicity or production of proinflammatory cytokines, such as gamma interferon (IFN-γ), upon parasite infection might also be beneficial to the parasite. In the present study, we investigated the effects of T. gondii infection on NK cells. In vitro, infected NK cells were found to be poor at killing target cells and had reduced levels of IFN-γ production. This could be attributed in part to the inability of infected cells to form conjugates with their target cells. However, even upon NK1.1 cross-linking of NK cells, the infected NK cells also exhibited poor degranulation and IFN-γ production. Similarly, NK cells infected in vivo were also poor at killing target cells and producing IFN-γ. Increased levels of transforming growth factor β production, as well as increased levels of expression of SHP-1 in the cytosol of infected NK cells upon infection, were observed in infected NK cells. However, the phosphorylation of STAT4 was not altered in infected NK cells, suggesting that transcriptional regulation mediates the reduced IFN-γ production, which was confirmed by quantitative PCR. These data suggest that infection of NK cells by T. gondii impairs NK cell recognition of target cells and cytokine release, two mechanisms that independently could enhance T. gondii survival.

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Dengue Virus-Infected Dendritic Cells, but Not Monocytes, Activate Natural Killer Cells through a Contact-Dependent Mechanism Involving Adhesion Molecules

mBio ◽

10.1128/mbio.00741-17 ◽

2017 ◽

Vol 8 (4) ◽

Cited By ~ 25

Author(s):

Vivian Vasconcelos Costa ◽

Weijian Ye ◽

Qingfeng Chen ◽

Mauro Martins Teixeira ◽

Peter Preiser ◽

...

Keyword(s):

Dendritic Cells ◽

Virus Infection ◽

Dengue Virus ◽

Nk Cells ◽

Adhesion Molecules ◽

Cell Activation ◽

Nk Cell ◽

Denv Infection ◽

Ifn Γ

ABSTRACT Natural killer (NK) cells play a protective role against dengue virus (DENV) infection, but the cellular and molecular mechanisms are not fully understood. Using an optimized humanized mouse model, we show that human NK cells, through the secretion of gamma interferon (IFN-γ), are critical in the early defense against DENV infection. Depletion of NK cells or neutralization of IFN-γ leads to increased viremia and more severe thrombocytopenia and liver damage in humanized mice. In vitro studies using autologous human NK cells show that DENV-infected monocyte-derived dendritic cells (MDDCs), but not monocytes, activate NK cells in a contact-dependent manner, resulting in upregulation of CD69 and CD25 and secretion of IFN-γ. Blocking adhesion molecules (LFA-1, DNAM-1, CD2, and 2β4) on NK cells abolishes NK cell activation, IFN-γ secretion, and the control of DENV replication. NK cells activated by infected MDDCs also inhibit DENV infection in monocytes. These findings show the essential role of human NK cells in protection against acute DENV infection in vivo, identify adhesion molecules and dendritic cells required for NK cell activation, and delineate the sequence of events for NK cell activation and protection against DENV infection. IMPORTANCE Dengue is a mosquito-transmitted viral disease with a range of symptoms, from mild fever to life-threatening dengue hemorrhagic fever. The diverse disease manifestation is thought to result from a complex interplay between viral and host factors. Using mice engrafted with a human immune system, we show that human NK cells inhibit virus infection through secretion of the cytokine gamma interferon and reduce disease pathogenesis, including depletion of platelets and liver damage. During a natural infection, DENV initially infects dendritic cells in the skin. We find that NK cells interact with infected dendritic cells through physical contact mediated by adhesion molecules and become activated before they can control virus infection. These results show a critical role of human NK cells in controlling DENV infection in vivo and reveal the sequence of molecular and cellular events that activate NK cells to control dengue virus infection. IMPORTANCE Dengue is a mosquito-transmitted viral disease with a range of symptoms, from mild fever to life-threatening dengue hemorrhagic fever. The diverse disease manifestation is thought to result from a complex interplay between viral and host factors. Using mice engrafted with a human immune system, we show that human NK cells inhibit virus infection through secretion of the cytokine gamma interferon and reduce disease pathogenesis, including depletion of platelets and liver damage. During a natural infection, DENV initially infects dendritic cells in the skin. We find that NK cells interact with infected dendritic cells through physical contact mediated by adhesion molecules and become activated before they can control virus infection. These results show a critical role of human NK cells in controlling DENV infection in vivo and reveal the sequence of molecular and cellular events that activate NK cells to control dengue virus infection.

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CX3CR1 expression defines 2 KLRG1+ mouse NK-cell subsets with distinct functional properties and positioning in the bone marrow

Blood ◽

10.1182/blood-2010-07-297101 ◽

2011 ◽

Vol 117 (17) ◽

pp. 4467-4475 ◽

Cited By ~ 31

Author(s):

Giuseppe Sciumè ◽

Giulia De Angelis ◽

Giorgia Benigni ◽

Andrea Ponzetta ◽

Stefania Morrone ◽

...

Keyword(s):

Bone Marrow ◽

Nk Cells ◽

Cell Population ◽

Nk Cell ◽

Target Cells ◽

Functional Features ◽

Ifn Γ ◽

Cell Positioning ◽

Cytokine Stimulation ◽

Cx3cr1 Expression

Abstract During development in the bone marrow (BM), NK-cell positioning within specific niches can be influenced by expression of chemokine or adhesion receptors. We previously demonstrated that the maintenance in the BM of selected NK-cell subsets is regulated by the CXCR4/CXCL12 axis. In the present study, we showed that CX3CR1 is prevalently expressed on KLRG1+ NK cells, a subset considered terminally differentiated. Two KLRG1+ NK-cell populations endowed with distinct homing and functional features were defined according to CX3CR1 expression. In the BM, KLRG1+/CX3CR1− NK cells were mainly positioned into parenchyma, while KLRG1+/CX3CR1+ NK cells exhibited reduced CXCR4 expression and were preferentially localized in the sinusoids. We also showed that α4 integrin plays a pivotal role in the maintenance of NK cells in the BM sinusoids and that α4 neutralization leads to strong reduction of BM KLRG1+/CX3CR1+ NK cells. Moreover, we found that KLRG1+/CX3CR1+ cells originate from KLRG1+/CX3CR1− NK-cell population and display impaired capability to produce IFN-γ and to lyse YAC-1 target cells on cytokine stimulation. Altogether, our findings show that CX3CR1 represents a marker of a KLRG1+ NK-cell population with unique properties that can irreversibly differentiate from the KLRG1+/CX3CR1− NK cells during steady state conditions.

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Natural-killer cells and dendritic cells: “l'union fait la force”

Blood ◽

10.1182/blood-2005-03-1154 ◽

2005 ◽

Vol 106 (7) ◽

pp. 2252-2258 ◽

Cited By ~ 386

Author(s):

Thierry Walzer ◽

Marc Dalod ◽

Scott H. Robbins ◽

Laurence Zitvogel ◽

Eric Vivier

Keyword(s):

Dendritic Cells ◽

Nk Cells ◽

Natural Killer ◽

Cell Activation ◽

Nk Cell ◽

Interleukin 12 ◽

Cell Contact ◽

Ifn Γ

AbstractSeveral recent publications have focused on the newly described interactions between natural-killer (NK) cells and dendritic cells (DCs). Activated NK cells induce DC maturation either directly or in synergy with suboptimal levels of microbial signals. Immature DCs appear susceptible to autologous NK-cell-mediated cytolysis while mature DCs are protected. NK-cell-induced DC activation is dependent on both tumor necrosis factor-α (TNF-α)/interferon-γ (IFN-γ) secretion and a cell-cell contact involving NKp30. In vitro, interleukin-12 (IL-12)/IL-18, IL-15, and IFN-α/β production by activated DCs enhance, in turn, NK-cell IFN-γ production, proliferation, and cytotoxic potential, respectively. In vivo, NK-cell/DC interactions may occur in lymphoid organs as well as in nonlymphoid tissues, and their consequences are multiple. By inducing DC activation, NK-cell activation induced by tumor cells can indirectly promote antitumoral T-cell responses. Reciprocally, DCs activated through Toll-like receptors (TLRs) induce potent NK-cell activation in antiviral responses. Thus, DCs and NK cells are equipped with complementary sets of receptors that allow the recognition of various pathogenic agents, emphasizing the role of NK-cell/DC crosstalk in the coordination of innate and adaptive immune responses.

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AFM13 Is the Most Advanced Bispecific NK-Cell Engaging Antibody in Clinical Development Substantially Enhancing NK-Cell Effector Function and Proliferation

Blood ◽

10.1182/blood.v128.22.1764.1764 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1764-1764 ◽

Cited By ~ 1

Author(s):

Jens Pahl ◽

Uwe Reusch ◽

Thorsten Gantke ◽

Anne Kerber ◽

Joachim Koch ◽

...

Keyword(s):

Nk Cells ◽

Cell Activation ◽

Nk Cell ◽

Target Cells ◽

Cell Cytotoxicity ◽

Cell Receptors ◽

Cell Responses ◽

Nk Cell Receptors ◽

Ifn Γ ◽

Nk Cell Cytotoxicity

Abstract Introduction: AFM13 is an NK-cell engaging CD30/CD16A bispecific tetravalent TandAb antibody currently in phase 2 clinical development in Hodgkin lymphoma (HL) and other CD30+ malignancies. It engages NK-cells through CD16A with high affinity and specificity and confers significantly stronger NK-cell activation compared to other therapeutic antibodies. We have previously shown synergistic efficacy when NK-cell activation by AFM13 is combined with check-point modulation such as anti-PD-1 treatment, which is known to unleash T cell and NK-cell activity. The goal of this study was to identify further candidates for combination treatments and biomarkers that potentially indicate NK-cell responses to AFM13 treatment. Methods: AFM13-mediated NK-cell cytotoxicity and IFN-γ production after 4-hour interaction with HL cell lines was measured by 51Cr release assays and flow cytometry, respectively. Expression of NK-cell receptors, NK-cell proliferation (CFSE dilution) and expansion (absolute cell counts) was analyzed by flow cytometry. Results: The interaction of NK-cells with AFM13-coated tumor cells up-regulated the expression of NK-cell receptors such as CD25, CD69, CD137/4-1BB as well as molecules that may serve as NK-cell check-points when compared with the unrelated NK-cell binding TandAb AFM12 that does not bind to target cells. Importantly, CD16A engagement by AFM13 enhanced the proliferation and expansion potential of NK-cells when subsequently incubated with IL-15 or with particularly low doses of IL-2. NK-cell cytotoxicity and IFN-γ production was substantially increased towards CD30+ tumor cells in the presence of AFM13. Even target cells resistant to naïve and IL-2/IL-15-activated NK-cells were susceptible to AFM13-induced NK-cell cytotoxicity. AFM13 concentrations of as low as 10-2 µg/mL resulted in maximal activity while AFM13 was significantly more potent than native anti-CD30 IgG1 antibody. NK-cell activation by IL-2 or IL-15 had a synergistic effect on AFM13-mediated cytotoxicity. Conclusion: AFM13 specifically enhances the cytotoxic, proliferative and cytokine-producing potential of NK-cells. Our data indicate that the distinctive modulation of NK-cell receptors can be utilized to monitor NK-cell responses during AFM13 therapy and provides candidates for therapeutic combination strategies. Moreover, the combination with low doses of IL-2 or with IL-15 may expand the quantity of tumor-reactive NK-cells after AFM13 treatment and promote NK-cell functionality in the tumor microenvironment in cancer patients. Disclosures Reusch: Affimed: Employment, Patents & Royalties: Patents. Gantke:Affimed GmbH: Employment. Kerber:Affimed: Employment. Koch:Affimed: Employment. Treder:Affimed: Employment. Cerwenka:Affimed: Research Funding.

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Natural killer (NK) cell activation, cytokine production, and cytotoxicity in human PBMC/myeloma cell co-culture exposed to elotuzumab (Elo) alone or in combination with lenalidomide (Len).

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.8087 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 8087-8087 ◽

Cited By ~ 2

Author(s):

Balaji Balasa ◽

Rui Yun ◽

Nicole Belmar ◽

Gary Starling ◽

Audie Rice

Keyword(s):

Nk Cells ◽

Cell Activation ◽

Nk Cell ◽

Myeloma Cell ◽

Cell Killing ◽

Cell Counting ◽

Target Cells ◽

Human Pbmc ◽

Myeloma Cells ◽

Ifn Γ

8087 Background: Elo is a monoclonal IgG1 antibody targeting CS1, a cell surface glycoprotein highly expressed on >95% of myeloma cells. In preclinical models Elo exerts anti-myeloma activity via NK cell-mediated antibody-dependent cellular cytotoxicity. Len is an immunomodulatory agent that may activate NK cells. The combination of Elo + Len synergistically enhanced anti-tumor activity in myeloma xenograft models. We investigated the mechanism of enhancing NK cell activation and myeloma cell killing with Elo + Len. Methods: Human PBMC/OPM-2 co-cultures were treated for 24-72h with Elo, Len, or Elo + Len. Activation markers and adhesion receptors were evaluated by flow cytometry. Cytokines were measured by Luminex and ELISpot assays. Cytotoxicity was assessed by cell counting. Results: Elo + Len increased IFN-γ secretion significantly more than Elo or Len alone. IFN-γ elevates ICAM-1 expression, and ICAM-1 surface expression on OPM-2 target cells increased synergistically with Elo + Len. Elo, Elo + Len but not Len increased expression of CD25 (IL-2Rα) on NK cells. Len increased the levels of IL-2, but those were decreased in the presence of Elo due to increased consumption by CD25 expressing NK cells. Blocking uptake of IL-2 with anti-CD25 resulted in higher IL-2 levels than with Len. ELISpot assays confirmed that Elo + Len significantly increased the number of IL-2-producing cell colonies compared with Elo or Len. Elo induced NK dependent myeloma cell killing, and the effect was significantly higher with Elo + Len. Conclusions: Elo alone activated NK cells and mediated the killing of myeloma cells in PBMC/OPM-2 co-cultures. Elo + Len synergistically enhanced myeloma cell killing and increased expression/production of IFN-γ, ICAM-1, IL-2, and CD25. [Table: see text]

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Vaccination with Live Leishmania major and CpG DNA Promotes Interleukin-2 Production by Dermal Dendritic Cells and NK Cell Activation

Clinical and Vaccine Immunology ◽

10.1128/cvi.00249-09 ◽

2009 ◽

Vol 16 (11) ◽

pp. 1601-1606 ◽

Cited By ~ 10

Author(s):

Eva Maria Laabs ◽

Wenhui Wu ◽

Susana Mendez

Keyword(s):

Dendritic Cells ◽

Nk Cells ◽

Cell Activation ◽

Leishmania Major ◽

Nk Cell ◽

Natural Infection ◽

Interleukin 2 ◽

Innate Immune Responses ◽

Cpg Dna ◽

Ifn Γ

ABSTRACT Cutaneous leishmaniasis due to Leishmania major is an emerging, chronic parasitic disease that causes disfigurement and social stigmatization. Drug therapy is inadequate, and there is no vaccine. Inoculation of virulent parasites (leishmanization) is the only intervention that has ever provided protection, because it mimics natural infection and immunity, but it was discontinued due to safety concerns (uncontrolled vaccinal lesions). In an effort to retain the benefits (immunity) while avoiding the side effects (lesions) of leishmanization, we immunized C57BL/6 mice with L. major and CpG DNA (Lm/CpG). This combination prevented lesions while inducing immunity. Also, the vaccination with live parasites and the Toll-like receptor 9 agonist enhanced innate immune responses by activating dermal dendritic cells (DCs) to produce cytokines. Here we report that the Lm/CpG vaccine induced dermal DCs, but not bone marrow-derived DCs, to produce interleukin-2 (IL-2). The release of this unusual DC-derived cytokine was concomitant with a peak in numbers of NK cells that produced gamma interferon (IFN-γ) and also enhanced activation of proliferation of IFN-γ+ CD4+ T cells. Parasite growth was controlled in Lm/CpG-vaccinated animals. This is the first demonstration of the ability of dermal DCs to produce IL-2 and of the activation of NK cells by vaccination in the context of leishmaniasis. Understanding how the Lm/CpG vaccine enhances innate immunity may provide new tools to develop vaccines against L. major, other chronic infectious diseases, or other conditions, such as cancer.

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Ifosfamide impairs the allostimulatory capacity of human dendritic cells by intracellular glutathione depletion

Blood ◽

10.1182/blood-2003-05-1408 ◽

2003 ◽

Vol 102 (10) ◽

pp. 3668-3674 ◽

Cited By ~ 33

Author(s):

Maria C. Kuppner ◽

Anabel Scharner ◽

Valeria Milani ◽

Christoph von Hesler ◽

Katharina E. Tschöp ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Nk Cells ◽

Cell Function ◽

Nk Cell ◽

Human Monocyte ◽

Glutathione Depletion ◽

Intracellular Glutathione ◽

Ifn Γ

AbstractIfosfamide, a clinically potent chemotherapeutic agent, causes the depletion of intracellular glutathione (GSH) levels in various cell types. GSH is the major intracellular reductant against oxidative stress. 4-Hydroxyifosfamide (4-OH-IF), the activated form of ifosfamide, depletes GSH levels in T cells and natural killer (NK) cells; this is accompanied by a decrease in T-cell and NK-cell function. Here we demonstrate for the first time that human monocyte-derived dendritic cells (DCs) express higher constitutive levels of GSH and are less sensitive to 4-OH-IF-induced GSH depletion than T cells and NK cells. Treatment of DCs with 4-OH-IF significantly reduced their ability to stimulate allogeneic T-cell proliferation and interferon-γ (IFN-γ) production. Ifosfamide also decreased DC interleukin-12p70 (IL-12p70) production after stimulation with lipopolysaccharide (LPS) and IFN-γ. The decrease in allostimulatory capacity and in IFN-γ and IL-12 production correlated with a decrease in intracellular GSH in the DCs. The responses could be restored by reconstituting DC GSH levels with glutathione monoethyl ester (GSH-OEt). 4-OH-IF had no inhibitory effect on the ability of DCs to present exogenously added tyrosinase peptide to tyrosinase-specific cytotoxic T lymphocytes (CTLs). These studies suggest that in cancer patients treated with ifosfamide, protection strategies based on glutathione reconstitution may enhance DC function. (Blood. 2003;102: 3668-3674)

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Coxiella burnetii-Infected NK Cells Release Infectious Bacteria by Degranulation

Infection and Immunity ◽

10.1128/iai.00172-20 ◽

2020 ◽

Vol 88 (11) ◽

Author(s):

Svea Matthiesen ◽

Luca Zaeck ◽

Kati Franzke ◽

Rico Jahnke ◽

Charlie Fricke ◽

...

Keyword(s):

Nk Cells ◽

Coxiella Burnetii ◽

Defense Mechanism ◽

Cell Types ◽

Chlamydia Psittaci ◽

Content Type ◽

Lytic Granules ◽

Self Defense ◽

Different Types ◽

Ifn Γ

ABSTRACT Natural killer (NK) cells are critically involved in the early immune response against various intracellular pathogens, including Coxiella burnetii and Chlamydia psittaci. Chlamydia-infected NK cells functionally mature, induce cellular immunity, and protect themselves by killing the bacteria in secreted granules. Here, we report that infected NK cells do not allow intracellular multiday growth of Coxiella, as is usually observed in other host cell types. C. burnetii-infected NK cells display maturation and gamma interferon (IFN-γ) secretion, as well as the release of Coxiella-containing lytic granules. Thus, NK cells possess a potent program to restrain and expel different types of invading bacteria via degranulation. Strikingly, though, in contrast to Chlamydia, expulsed Coxiella organisms largely retain their infectivity and, hence, escape the cell-autonomous self-defense mechanism in NK cells.

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Tim-3 expression and function in natural killer cells from advanced melanoma patients.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.8571 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 8571-8571

Author(s):

Ines Esteves Domingues Pires Da Silva ◽

Sonia Jimenez-Baranda ◽

Anne Gallois ◽

Vijay Kuchroo ◽

Iman Osman ◽

...

Keyword(s):

Nk Cells ◽

Nk Cell ◽

Advanced Melanoma ◽

Target Cells ◽

Cell Cytotoxicity ◽

Healthy Donors ◽

Melanoma Patients ◽

Ifn Γ ◽

Nk Cell Cytotoxicity ◽

And Function

8571 Background: The concept of CD8+ T cell exhaustion in the context of metastatic cancer has been reinforced by the recent success of immunotherapies targeting the exhaustion markers CTLA-4 and PD-1 in advanced melanoma. T-cell immunoglobulin 3 (Tim-3), another exhaustion marker, is also expressed in natural killer (NK) cells, however its role is still unknown. Recent reports have shown that NK cells, innate immune cells that eliminate tumors through cytotoxicity and IFN-g production, are functionally impaired in advanced melanoma patients, although no receptor has been linked with that phenotype so far. In this study, we characterize the role of Tim-3 in NK cells, particularly in the presence of its natural ligand, Galectin-9 (Gal-9), that is known to be expressed/secreted by some tumor cells including melanoma. Methods: We compared 20 advanced melanoma donors NK cells with 40 healthy donors NK cells as it relates to Tim-3 expression (by flow cytometry) and function (cytotoxicity, IFN-γ production and proliferation). NK cells cytotoxicity was measured by lamp-1 expression, and two different target cells were used: i) K562 cells (Gal-9-) and ii) Gmel Gal-9+ and Gmel Gal-9- sorted melanoma cells. Proliferation was quantified by CFSE after 6 days in the presence of rhIL-2. Recombinant rhGal9 effect was tested in cytotoxicity and IFN-γ production. Results: Melanoma patients NK cells express higher levels of Tim-3 compared to healthy donors NK cells (p<0.05). Melanoma patients NK cells have a defect in cytotoxicity, proliferation and IFN-γ production. Tim-3 expression by itself (without engagement of specific ligands) does not negatively affect NK cell functions (p<0.05). However, when rhGal9 is added to the system, a decrease in NK cell cytotoxicity and IFN-γ production (p<0.05) was observed. Finally, the expression of Gal-9 by the target cells induces a defect in NK cell cytotoxicity (Gmel Gal-9+ vs Gmel Gal-9-). Conclusions: These data suggest that advanced melanoma patients NK cells are exhausted, although it still remains unclear if Tim-3 is involved in this phenotype. In addition,the expression/secretion of Galectin-9, immunosuppressive for NK cells, may be a possible mechanism for tumors to evade immune surveillance.

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