Vimentin expressed on <i>Mycobacterium tuberculosis</i>-infected human monocytes is involved in binding to the NKp46 receptor

Garg, A.; Barnes, P. F.; Porgador, A.; Roy, S.; Wu, S.; Nanda, J. S.; Griffith, D. E.; Girard, W. M.; Rawal, N.; Shetty, S.; Vankayalapati, R.

doi:10.4049/jimmunol.181.12.8797

Cited by 54 publications

(66 citation statements)

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“…9). Although we cannot rule out the possibility that NKp46 binds additional cellular ligand(s) induced by the virus (75) or that HA may serve as a ligand for other NK receptors, our results are consistent with previous reports suggesting that HA is a ligand for NKp46 (43,44). Moreover, we extend these original findings by placing potential NKp46-HA interactions in the context of NK-DC cooperation (76).…”

Section: Discussionsupporting

confidence: 90%

NKp46 and NKG2D Recognition of Infected Dendritic Cells Is Necessary for NK Cell Activation in the Human Response to Influenza Infection

Draghi

Pashine

Sanjanwala

et al. 2007

The Journal of Immunology

181

169

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At an early phase of viral infection, contact and cooperation between dendritic cells (DCs) and NK cells activates innate immunity, and also influences recruitment, when needed, of adaptive immunity. Influenza, an adaptable fast-evolving virus, annually causes acute, widespread infections that challenge the innate and adaptive immunity of humanity. In this study, we dissect and define the molecular mechanisms by which influenza-infected, human DCs activate resting, autologous NK cells. Three events in NK cell activation showed different requirements for soluble mediators made by infected DCs and for signals arising from contact with infected DCs. IFN-α was mainly responsible for enhanced NK cytolysis and also important for CD69 up-regulation, whereas IL-12 was necessary for enhancing IFN-γ production. Increased CD69 expression and IFN-γ production, but not increased cytolysis, required recognition of influenza-infected DCs by two NK cell receptors: NKG2D and NKp46. Abs specific for these receptors or their known ligands (UL16-binding proteins 1–3 class I-like molecules for NKG2D and influenza hemagglutinin for NKp46) inhibited CD69 expression and IFN-γ production. Activation of NK cells by influenza-infected DCs and polyinosinic:polycytidylic acid (poly(I:C))-treated DCs was distinguished. Poly(I:C)-treated DCs did not express the UL16-binding protein 3 ligand for NKG2D, and in the absence of the influenza hemagglutinin there was no involvement of NKp46.

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Section: Discussionsupporting

confidence: 90%

NKp46 and NKG2D Recognition of Infected Dendritic Cells Is Necessary for NK Cell Activation in the Human Response to Influenza Infection

Draghi

Pashine

Sanjanwala

et al. 2007

The Journal of Immunology

181

169

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“…7A). In concordance with Garg et al [30], we confirmed that vimentin is an NKp46 ligand, as antivimentin Ab could block the binding of NKp46-Ig fusion protein on PHA-activated CD4 1 T cells (Fig. 7B).…”

Section: Nk Cells Killed Activated Cd4 1 T Cells Through Nkp46-vimentsupporting

confidence: 92%

“…Thus, the increased cytotoxicity of AC-treated NK cells was independent to PS on AC. [30]. Therefore, we investigated the surface expression of vimentin on activated CD4 1 T cells and its role in mediating NK cell cytotoxicity.…”

Section: Ac Jur -Treated Nk Cells Mediated Lysis Of Autologousactivatmentioning

confidence: 99%

“…Vimentin, an intermediate filament protein expressed on the surface of Sezary cells [28], TNF-a-activated macrophages [29] and Mycobacterium tuberculosis-infected monocytes [30], has been reported as an NKp46 ligand that can induce the cytolytic activity of NK cells [30]. Therefore, we investigated the surface expression of vimentin on activated CD4 1 T cells and its role in mediating NK cell cytotoxicity.…”

Section: Nk Cells Killed Activated Cd4 1 T Cells Through Nkp46-vimentmentioning

confidence: 99%

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Natural killer cells become tolerogenic after interaction with apoptotic cells

et al. 2010

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NK cells are effectors in innate immunity and also participate in immunoregulation through the release of TGF-b1 and lysis of activated/autoreactive T cells. Apoptotic cells (AC) have been shown to induce tolerogenic properties in innate immune cells, including macrophages and dendritic cells, but not NK cells. In this study, we demonstrated that after interaction with AC, NK cells released TGF-b1, which in turn suppressed the production of IFN-c by NK cells upon IL-12 and IgG activation. We further identified phosphatidylserine as a potential target on AC for the NK cells, as phosphatidylserine could stimulate NK cells to release TGF-b1, which in turn suppressed CD4 1 T-cell proliferation and activation. Moreover, AC-treated NK cells displayed cytotoxicity against autologous-activated CD4 1 T cells by upregulating NKp46. This lysis occurred in part through the NKp46-vimentin pathway, as activated CD4 1 T cells expressed vimentin on the cell surface and blocking of vimentin or NKp46, but not other NK-cell receptors, significantly suppressed the NK-cell cytotoxicity. We report here a novel interaction between NK cells and AC, resulting in the tolerogenic properties of NK cells required for immune contraction.Key words: Apoptosis . NK cells . Tolerance Supporting Information available online Introduction NK cells are the front line players of innate immunity, involved in eliminating virus-infected cells and transformed cells [1]. NK cells also promote inflammation through the release of high levels of pro-inflammatory cytokines and chemokines. Recent observations show that NK cells are also important in immune regulation and thus serve as a link between innate and adaptive immunity [2]. NK cells could regulate immune responses by producing cytokines, including IFN-g, . Martin-Fontecha et al. further demonstrated that NK cells also release IFN-g for Th1 polarization in vivo [4]. Moreover, activated NK cells could acquire an APC phenotype with upregulation of CD86 and MHC class II molecules to enhance T-cell proliferation and activation [5].Although NK cells participate in promoting inflammation and Th1 polarization, deficient NK cell functions and cytotoxicity are associated with autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis and multiple sclerosis [6,7]. These observations suggest that NK cells help maintain homeostasis of the immune system. NK cells may play a role in peripheral tolerance as they can secrete , which is further enhanced by coculturing with anti-CD2 Ab [9] and soluble HLA-I [10]. In vivo mouse model confirmed that TGF-b1-producing NK cells can inhibit Th1 response by suppressing IFN-g production [11]. Furthermore, NK cells display cytolytic activity against autologous immune cells, such as DC and T cells. Lysis of immature DC by NK cells through NKp30 may limit the number of mature DC and prevent over presentation of antigens to 1718T cells [12]. NK cells also eliminate autoreactive T cells in EAE mouse model, resulting in reduced disease severity [13,14]. Cerb...

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“…6,7 Only a few ligands for the NCRs have been identified to date. [8][9][10][11][12][13][14] Surprisingly, among novel ligands for NKp30 (BAG6 [BAT3], 10 B7-H6 11 ), NKp44 (proliferating cell nuclear antigen 12 ) and NKp46 (vimentin 13,14 ), only B7-H6 is a surface membrane ligand. BAG6, proliferating cell nuclear antigen, and vimentin are proteins without any classical transmembrane domain and are known to exert divergent intracellular functions, including protein sorting and transport, proliferation, and apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Soluble ligands for NK cell receptors promote evasion of chronic lymphocytic leukemia cells from NK cell anti-tumor activity

Reiners¹,

Topolar²,

Henke³

et al. 2013

Blood

186

171

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Key Points• Exosomal NKp30-ligand BAG6 is crucial for detection of tumor cells by NK cells in vitro and in vivo.• Soluble plasma factors including BAG6 suppress NK cell cytotoxicity and promote evasion of CLL cells from NK cell anti-tumor activity.Natural killer (NK) cells are a major component of the anti-tumor immune response. NK cell dysfunctions have been reported in various hematologic malignancies, including chronic lymphocytic leukemia (CLL). Here we investigated the role of tumor cellreleased soluble and exosomal ligands for NK cell receptors that modulate NK cell activity. Soluble CLL plasma factors suppressed NK cell cytotoxicity and downregulated the surface receptors CD16 and CD56 on NK cells of healthy donors. The inhibition of NK cell cytotoxicity was attributed to the soluble ligand BAG6/BAT3 that engages the activating receptor NKp30 expressed on NK cells. Soluble BAG6 was detectable in the plasma of CLL patients, with the highest levels at the advanced disease stages. In contrast, NK cells were activated when BAG6 was presented on the surface of exosomes. The latter form was induced in non-CLL cells by cellular stress via an nSmase2-dependent pathway. Such cells were eliminated by lymphocytes in a xenograft tumor model in vivo. Here, exosomal BAG6 was essential for tumor cell killing because BAG6-deficient cells evaded immune detection. Taken together, the findings show that the dysregulated balance of exosomal vs soluble BAG6 expression may cause immune evasion of CLL cells. (Blood. 2013;121(18):3658-3665) IntroductionChronic lymphocytic leukemia (CLL) patients suffer from severe immune defects resulting in increased susceptibility to infections and failure to generate an anti-tumor immune response. 1 Natural killer (NK) cells, lymphocytes of the innate immune system, are considered to be a major component of the immunosurveillance in leukemia. [2][3][4] However, little is known about the functionality of NK cells and their role in tumor immune escape in CLL.NK cells are tightly regulated by inhibitory or activating "missing self" and "induced self" signals sensed via cell surface receptors. 5 The best examined activating receptors are the Fc receptor CD16, NKG2D, and the natural cytotoxicity receptors (NCRs) NKp30, NKp44, and NKp46. Known ligands for NKG2D are the major histocompatibility complex (MHC) class I-related molecules MICA/B and the UL16-binding proteins (ULBP1, ULBP2, ULBP3, ULBP4, ULBP5, and ULBP6) that are induced upon cellular stress on target cells. 6,7 Only a few ligands for the NCRs have been identified to date. [8][9][10][11][12][13][14] Surprisingly, among novel ligands for NKp30 (BAG6 [BAT3], 10 B7-H6 11 ), NKp44 (proliferating cell nuclear antigen 12 ) and NKp46 (vimentin 13,14 ), only B7-H6 is a surface membrane ligand. BAG6, proliferating cell nuclear antigen, and vimentin are proteins without any classical transmembrane domain and are known to exert divergent intracellular functions, including protein sorting and transport, proliferation, and apoptosis. It is still ...

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Vimentin expressed on Mycobacterium tuberculosis-infected human monocytes is involved in binding to the NKp46 receptor

Cited by 54 publications

References 0 publications

NKp46 and NKG2D Recognition of Infected Dendritic Cells Is Necessary for NK Cell Activation in the Human Response to Influenza Infection

NKp46 and NKG2D Recognition of Infected Dendritic Cells Is Necessary for NK Cell Activation in the Human Response to Influenza Infection

Natural killer cells become tolerogenic after interaction with apoptotic cells

Soluble ligands for NK cell receptors promote evasion of chronic lymphocytic leukemia cells from NK cell anti-tumor activity

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