scholarly journals Recruitment and Activation of Natural Killer (Nk) Cells in Vivo Determined by the Target Cell Phenotype

2000 ◽  
Vol 191 (1) ◽  
pp. 129-138 ◽  
Author(s):  
Rickard Glas ◽  
Lars Franksson ◽  
Clas Une ◽  
Maija-Leena Eloranta ◽  
Claes Öhlén ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Tumor Cells ◽  
Mhc Class I ◽  
Nk Cell ◽  
Interferon Γ ◽  
Class I ◽  
Cell Phenotype ◽  
Target Cells

Natural killer (NK) cells can spontaneously lyse certain virally infected and transformed cells. However, early in immune responses NK cells are further activated and recruited to tissue sites where they perform effector functions. This process is dependent on cytokines, but it is unclear if it is regulated by NK cell recognition of susceptible target cells. We show here that infiltration of activated NK cells into the peritoneal cavity in response to tumor cells is controlled by the tumor major histocompatibility complex (MHC) class I phenotype. Tumor cells lacking appropriate MHC class I expression induced NK cell infiltration, cytotoxic activation, and induction of transcription of interferon γ in NK cells. The induction of these responses was inhibited by restoration of tumor cell MHC class I expression. The NK cells responding to MHC class I–deficient tumor cells were ∼10 times as active as endogenous NK cells on a per cell basis. Although these effector cells showed a typical NK specificity in that they preferentially killed MHC class I–deficient cells, this specificity was even more distinct during induction of the intraperitoneal response. Observations are discussed in relation to a possible adaptive component of the NK response, i.e., recruitment/activation in response to challenges that only NK cells are able to neutralize.

scholarly journals MHC class I–deficient natural killer cells acquire a licensed phenotype after transfer into an MHC class I–sufficient environment

2010 ◽  
Vol 207 (10) ◽  
pp. 2073-2079 ◽  
Author(s):  
Julie M. Elliott ◽  
Joseph A. Wahle ◽  
Wayne M. Yokoyama
Keyword(s):  
Bone Marrow ◽  
Nk Cells ◽  
Natural Killer ◽  
Mhc Class I ◽  
Interferon Γ ◽  
Class I ◽  
Target Cells ◽  
Major Histocompatability Complex ◽  
Gain Of Function ◽  
Mhc Class I Molecule

In MHC class I–deficient hosts, natural killer (NK) cells are hyporesponsive to cross-linking of activation receptors. Functional competence requires engagement of a self–major histocompatability complex (MHC) class I–specific inhibitory receptor, a process referred to as “licensing.” We previously suggested that licensing is developmentally determined in the bone marrow. In this study, we find that unlicensed mature MHC class I–deficient splenic NK cells show gain-of-function and acquire a licensed phenotype after adoptive transfer into wild-type (WT) hosts. Transferred NK cells produce WT levels of interferon-γ after engagement of multiple activation receptors, and degranulate at levels equivalent to WT NK cells upon coincubation with target cells. Only NK cells expressing an inhibitory Ly49 receptor specific for a cognate host MHC class I molecule show this gain-of-function. Therefore, these findings, which may be relevant to clinical bone marrow transplantation, suggest that neither exposure to MHC class I ligands during NK development in the BM nor endogenous MHC class I expression by NK cells themselves is absolutely required for licensing.

Transfer of MHC Class I by Coating Platelets Enables Tumor Cells to Evade NK Cell Immune Surveillance by Conferring a “Pseudo Self” Phenotype

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 583-583 ◽  
Author(s):  
Theresa Placke ◽  
Hans-Georg Kopp ◽  
Martin Schaller ◽  
Gundram Jung ◽  
Lothar Kanz ◽  
...  
Keyword(s):  
T Cell ◽  
Nk Cells ◽  
Tumor Cells ◽  
Mhc Class I ◽  
Nk Cell ◽  
Immune Surveillance ◽  
Class I ◽  
Immunofluorescent Staining ◽  
Target Cells ◽  
Missing Self

Abstract Abstract 583 NK cells are a central component of the cytotoxic lymphocyte compartment capable of lysing tumor cells without prior immune sensitization of the host. The mechanisms leading to activation of NK reactivity are described by the principles of ‘missing-self' and ‘induced-self', which imply that cells with a low or absent expression of MHC class I (‘missing-self') and/or a stress-induced expression of ligands of activating NK receptors like e.g. NKG2D (‘induced-self') are preferentially recognized and eliminated by NK cells. Thus, a balance of various activating and inhibitory signals determines whether NK cell responses are initiated or not. Tumor cells often downregulate expression of MHC class I to evade T cell-mediated immune surveillance, which results in enhanced NK susceptibility. Besides the direct interaction with their target cells, NK activity is further influenced by the reciprocal interplay with various other hematopoietic cells. We and others demonstrated previously that thrombocytopenia inhibits metastasis in murine models, which is reversed by additional depletion of NK cells (e.g., Jin et al., Nature Med. 2006, Palumbo et al., Blood 2005). However, the mechanisms by which platelets impair NK-tumor interaction are largely unclear, especially in humans. Recently we reported that platelets release TGF-β upon interaction with tumor cells causing downregulation of NKG2D on NK cells, which impairs anti-tumor immunity by disturbing the principle of “induced self” (Kopp et al., Cancer Res. 2009). Here we demonstrate that platelets further enable tumor cells to evade NK cell immune surveillance by preventing detection of “missing self”: We found that tumor cells rapidly get coated in the presence of platelets, the latter expressing large amounts of MHC class I on their surface. In case of MHC class I-negative or -low cancer cells, this process results in MHC class I “pseudoexpression” on the tumor cell surface as revealed by flow cytometry, immunofluorescent staining, and electron microscopy. Platelet-derived MHC class I was found to inhibit the reactivity of autologous NK, both upon activation with cytokines and, most importantly, in cultures with platelet-coated tumor cells. Using constitutively MHC class I-negative/low tumor cells we found that blocking MHC class I restored NK cytotoxicity and IFN-γ production against platelet-coated tumor cells, but did not alter NK reactivity against the tumor cells in the absence of coating platelets. Taken together, our data indicate that platelets enable a molecular mimicry of tumor cells, allowing the latter to downregulate MHC class I in order to escape T cell immunity without inducing sufficient NK tumor immune surveillance due to conferred platelet-mediated “pseudo self”. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Inhibitory Receptors Alter Natural Killer Cell Interactions with Target Cells Yet Allow Simultaneous Killing of Susceptible Targets

1999 ◽  
Vol 190 (7) ◽  
pp. 1005-1012 ◽  
Author(s):  
Mikael Eriksson ◽  
Guenther Leitz ◽  
Erik Fällman ◽  
Ove Axner ◽  
James C. Ryan ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Mhc Class I ◽  
Optical Tweezers ◽  
Target Cell ◽  
Nk Cell ◽  
Killer Cell ◽  
Class I ◽  
Target Cells ◽  
Inhibitory Receptors

Inhibitory receptors expressed on natural killer (NK) cells abrogate positive signals upon binding corresponding major histocompatibility complex (MHC) class I molecules on various target cells. By directly micromanipulating the effector–target cell encounter using an optical tweezers system which allowed temporal and spatial control, we demonstrate that Ly49–MHC class I interactions prevent characteristic cellular responses in NK cells upon binding to target cells. Furthermore, using this system, we directly demonstrate that an NK cell already bound to a resistant target cell may simultaneously bind and kill a susceptible target cell. Thus, although Ly49-mediated inhibitory signals can prevent many types of effector responses, they do not globally inhibit cellular function, but rather the inhibitory signal is spatially restricted towards resistant targets.

Augmentation of antitumor effects by NK cell inhibitory receptor blockade in vitro and in vivo

Blood ◽  
2001 ◽  
Vol 97 (10) ◽  
pp. 3132-3137 ◽  
Author(s):  
Crystal Y. Koh ◽  
Bruce R. Blazar ◽  
Thaddeus George ◽  
Lisbeth A. Welniak ◽  
Christian M. Capitini ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Nk Cells ◽  
Tumor Cells ◽  
Mhc Class I ◽  
Nk Cell ◽  
Class I ◽  
Inhibitory Receptors ◽  
Antitumor Effects

Abstract Subsets of natural killer (NK) cells are characterized by the expression of inhibitory and/or stimulatory receptors specific for major histocompatibility complex (MHC) class I determinants. In mice, these include the Ly49 family of molecules. One mechanism by which tumor cells may evade NK cell killing is by expressing the appropriate MHC class I and binding inhibitory Ly49 receptors. Therefore, the question of whether blocking the interaction between the Ly49 inhibitory receptors on NK and MHC class I cells on tumor cells augments antitumor activity was investigated. Blockade of Ly49C and I inhibitory receptors using F(ab′)2 fragments of the 5E6 monoclonal antibody (mAb) resulted in increased cytotoxicity against syngeneic tumors and decreased tumor cell growth in vitro. The effect of 5E6 F(ab′)2 was specific for the MHC of the tumor, as the use of F(ab′)2 of the mAb against Ly49G2 failed to increase NK activity. Treatment of leukemia-bearing mice with 5E6 F(ab′)2 fragments or adoptive transfer of NK cells treated ex vivo with the F(ab′)2 resulted in significant increases in survival. These results demonstrate that blockade of NK inhibitory receptors enhances antitumor activity both in vitro and in vivo, suggesting that NK inhibitory receptors can be responsible for diminishing antitumor responses. Therefore, strategies to block inhibitory receptors may be of potential use in increasing the efficacy of immunotherapy.

Platelets Impair NK Cell Immunosurveillance Of Metastasizing Tumor Cells By Altering Surface Expression and Shedding Of Ligands For The Activating Immunoreceptor NKG2D

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3488-3488
Author(s):  
Stefanie Raab ◽  
Korbinian Nepomuk Kropp ◽  
Alexander Steinle ◽  
Lothar Kanz ◽  
Hans-Georg Kopp ◽  
...  
Keyword(s):  
Cell Surface ◽  
Tumor Cell ◽  
Nk Cells ◽  
Tumor Cells ◽  
Mhc Class I ◽  
Nk Cell ◽  
Surface Expression ◽  
Class I ◽  
Target Cells ◽  
Missing Self

Abstract NK cells play an important role in the immunosurveillance of tumor cells. The mechanisms leading to NK cell activation are described by the ‘missing-self’ and “induced-self’ hypotheses, implying that cells with low or absent expression of MHC class I and stress-induced expression of ligands for activating receptors like e.g. NKG2D (NKG2DL) are preferentially recognized and eliminated by NK cells. Besides the direct interaction with their target cells, NK activity is further influenced by various other hematopoietic cells. In mouse models, thrombocytopenia impairs metastasis, and this is reversed by additional depletion of NK cells. However, the knowledge regarding the molecular mechanisms by which platelets influence NK cells is still fragmentary. We recently reported that release of TGF-β by platelets upon their interaction with (metastasizing) tumor cells downmodulates NKG2D on NK cells (Kopp et al., Cancer Res. 2009; Placke et al., J Innate Immun. 2011). Moreover, platelets transfer “healthy” MHC class I to the tumor cell surface. Thus, platelets may facilitate metastasis by interfering with both, “induced and missing self’ NK cell recognition. Here we provide evidence for a yet unknown mechanism by which platelets further impair NKG2D-mediated immunosurveillance. Tumor cells were incubated with platelets from healthy donors resulting in coating of tumor cells and activation of the platelets, or treated with platelet-derived soluble factors (releasate) obtained either by tumor cell-induced platelet activation (TCIPA) or the platelet agonist thrombin. Presence of platelet derived factors derived either from coating of tumor cells or contained in platelet releasate substantially reduced NKG2DL surface expression on tumor cells. This was paralleled by enhanced levels of soluble NKG2DL in culture supernatants, indicating that platelet-derived factors mediate NKG2DL shedding from the tumor cell surface. Diminished NKG2DL surface expression resulted in decreased NKG2D-dependent cytotoxicity of NK cells as revealed by blocking experiments using NKG2D antibody and NKG2DL-specific F(ab)2 fragments targeting the specific modulated NKG2DL. Our data thus identify induction of NKG2DL shedding as novel mechanism by which interaction of platelets with metastasizing tumor cells impairs NK cell immunosurveillance. Disclosures: No relevant conflicts of interest to declare.

The strength of inhibitory input during education quantitatively tunes the functional responsiveness of individual natural killer cells

Blood ◽  
2009 ◽  
Vol 113 (11) ◽  
pp. 2434-2441 ◽  
Author(s):  
Petter Brodin ◽  
Tadepally Lakshmikanth ◽  
Sofia Johansson ◽  
Klas Kärre ◽  
Petter Höglund
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Mhc Class I ◽  
Nk Cell ◽  
Interferon Γ ◽  
Class I ◽  
Inhibitory Input ◽  
Missing Self ◽  
Functional Responsiveness ◽  
Mhc Class I Molecules

Natural killer (NK) cells express inhibitory receptors for major histocompatibility complex (MHC) class I. If self-MHC is down-regulated or absent, lack of inhibition triggers “missing self” killing. NK cells developing in the absence of MHC class I are hypo-responsive, demonstrating that MHC class I molecules are required for NK-cell education. Here, we show that the number and the type of MHC class I alleles that are present during NK-cell education quantitatively determine the frequency of responding NK cells, the number of effector functions in individual NK cells, and the amount of interferon-γ production in NK cells of specific Ly49 subsets. A relationship between the extent of inhibitory signals during education and functional responsiveness was corroborated by an enhanced probability of NK cells expressing more than one inhibitory receptor for a single host self–MHC class I allele to degranulate after activation. Our data suggest that the capacity of an individual NK cell to respond to stimulation is quantitatively controlled by the extent of inhibitory signals that are received from MHC class I molecules during NK-cell education.

scholarly journals Acquisition of External Major Histocompatibility Complex Class I Molecules by Natural Killer Cells Expressing Inhibitory Ly49 Receptors

2001 ◽  
Vol 194 (10) ◽  
pp. 1519-1530 ◽  
Author(s):  
Anna Sjöström ◽  
Mikael Eriksson ◽  
Cristina Cerboni ◽  
Maria H. Johansson ◽  
Charles L. Sentman ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Nk Cells ◽  
Natural Killer ◽  
Mhc Class I ◽  
Nk Cell ◽  
Indirect Evidence ◽  
Class I ◽  
Target Cells ◽  
Major Histocompatibility ◽  
Histocompatibility Complex

Murine natural killer (NK) cells express inhibitory Ly49 receptors specific for major histocompatibility complex (MHC) class I molecules. We report that during interactions with cells in the environment, NK cells acquired MHC class I ligands from surrounding cells in a Ly49-specific fashion and displayed them at the cell surface. Ligand acquisition sometimes reached 20% of the MHC class I expression on surrounding cells, involved transfer of the entire MHC class I protein to the NK cell, and was independent of whether or not the NK cell expressed the MHC class I ligand itself. We also present indirect evidence for spontaneous MHC class I acquisition in vivo, as well as describe an in vitro coculture system with transfected cells in which the same phenomenon occurred. Functional studies in the latter model showed that uptake of H-2Dd by Ly49A+ NK cells was accompanied by a partial inactivation of cytotoxic activity in the NK cell, as tested against H-2Dd-negative target cells. In addition, ligand acquisition did not abrogate the ability of Ly49A+ NK cells to receive inhibitory signals from external H-2Dd molecules. This study is the first to describe ligand acquisition by NK cells, which parallels recently described phenomena in T and B cells.

scholarly journals Inducible down-regulation of MHC class I results in natural killer cell tolerance

2018 ◽  
Vol 216 (1) ◽  
pp. 99-116 ◽  
Author(s):  
Michael D. Bern ◽  
Bijal A. Parikh ◽  
Liping Yang ◽  
Diana L. Beckman ◽  
Jennifer Poursine-Laurent ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Mhc Class I ◽  
Nk Cell ◽  
Class I ◽  
Cell Tolerance ◽  
Down Regulation ◽  
Mhc I ◽  
Missing Self

Natural killer (NK) cells are innate lymphocytes that are thought to kill cells that down-regulate MHC class I (MHC-I) through “missing-self” recognition. NK cells from B2m−/− mice that lack surface MHC-I, however, are not autoreactive as predicted by the missing-self hypothesis. As a result, it is unclear if MHC-I down-regulation in vivo induces NK cell reactivity or tolerance to missing-self. Here, we generated a floxed B2m mouse to acutely down-regulate MHC-I in vivo in a host that normally expresses MHC-I. Global down-regulation of MHC-I induced NK cell hyporesponsiveness and tolerance to missing-self without overt missing-self reactivity. In contrast, down-regulation of MHC-I on a small fraction of hematopoietic cells triggered missing-self reactivity. Surprisingly, down-regulation of MHC-I only on CD4+ T cells predominately induced tolerance to missing-self without resetting NK cell responsiveness. In this setting, inflammation triggered substantial missing-self reactivity. These results show that MHC-I down-regulation can induce either NK cell tolerance or killing in vivo and that inflammation promotes missing-self reactivity.

NK Cell Anti-Tumor Reactivity Is Impaired by Platelet-Derived TGF-B through NKG2D Downregulation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2859-2859
Author(s):  
Hans-Georg Kopp ◽  
Theresa Placke ◽  
Benjamin J Schmiedel ◽  
Lothar Kanz ◽  
Matthias Krusch ◽  
...  
Keyword(s):  
Nk Cells ◽  
Tumor Cells ◽  
Mhc Class I ◽  
Nk Cell ◽  
Class I ◽  
Target Cells ◽  
Soluble Factors ◽  
Tumor Dissemination ◽  
Platelet Releasate ◽  
Nk Cell Cytotoxicity

Abstract NK cells can recognize and eliminate malignant cells thereby preventing both local tumor progression and metastatic spread. Besides by the direct interaction with their target cells, NK cell activity is influenced by the interplay with other hematopoietic cells influencing the activity of both involved cell types. Recently, we and others demonstrated that thrombocytopenia inhibits metastasis in mice, which is dependent on the presence of NK cells as shown by NK cell depletion experiments (Jin et al., Nat Med2006, 12: 557; Nieswandt et al., Cancer Res1999, 59: 1295). These data suggest that thrombocytopenia indirectly inhibits tumor dissemination by allowing NK cells to exert their anti-tumor effector functions. However, yet nothing is known regarding the molecular mechanisms underlying platelet-NK cell interaction, especially in humans. Here we report that human platelets express high levels of MHC class I, and incubation of MHC class I-negative tumor cells with platelets induced formation of tumor cell-platelet aggregates resulting in tumor MHC class I “pseudoexpression” which can inhibit NK cell reactivity via KIR triggering. Furthermore, tumor cell-induced platelet aggregation, alike stimulation with classical platelet agonists such as thrombin or collagen, resulted in secretion of platelet-derived soluble factors (releasate) containing, among others, high levels of the immunoregulatory cytokine TGF-b. Presence of releasate in cocultures of NK cells and tumor target cells was found to mediate a substantial inhibition of NK cell cytotoxicity and IFN-g production. Of note, platelet releasate caused a marked downregulation of the activating immunoreceptor NKG2D expressed on NK cells, which was partially restored by a neutralizing TGF-b antibody. Confirming the functional relevance of this finding, neutralization of TGF-b in platelet releasate by the same antibody also partially restored both the impaired NK cell cytotoxicity and IFN-g production in cocultures with tumor cells. Taken together, our data demonstrate that platelets may substantially influence NK cell anti-tumor reactivity by various mechanisms including inhibition of NKG2D-mediated NK cell immunosurveillance. Further elucidation of platelet ability to confer expression of immunregulatory surface molecules to tumor cells and the various soluble factors carrying NK cell-modulatory activity may reveal novel targets to prevent tumor dissemination.

Coating of Tumor Cells by Platelets Confers Expression of Immunoregulatory Molecules Which Impair NK Cell Anti-Tumor Reactivity.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2993-2993
Author(s):  
Theresa Placke ◽  
Hans-Georg Kopp ◽  
Lothar Kanz ◽  
Helmut R Salih
Keyword(s):  
Nk Cells ◽  
Tumor Cells ◽  
Mhc Class I ◽  
Molecular Mechanisms ◽  
Nk Cell ◽  
Conflicts Of Interest ◽  
Class I ◽  
Leukemic Cells ◽  
Target Cells ◽  
Tumor Immune Escape

Abstract Abstract 2993 Poster Board II-970 NK cells play an important role in cancer immunosurveillance and may prevent tumor progression and metastasis due to their ability to mediate direct cellular cytotoxicity and by releasing immunoregulatory cytokines which shape adaptive immune responses. Their reactivity is governed by various activating and inhibitory molecules expressed on target cells and reciprocal interactions with other hematopoietic cells like dendritic cells. Platelets contribute to tumor immune escape, metastasis, and angiogenesis (e.g. Jin et al Nature Med. 2006). In mice, thrombocytopenia inhibits metastasis, and this is reversed by NK cell depletion suggesting that platelets are an important additional player in NK cell-tumor interaction. However, the knowledge regarding the molecular mechanisms by which platelets influence NK cells is fragmentary at best. We found recently that platelet release soluble factors, most notably TGF-β, upon interaction with tumor cells which mediates NK cell silencing through downregulation of the activating immunoreceptor NKG2D (Kopp et al., Cancer Res 2009, in press). However, immunoregulatory molecules residing in the platelet membrane may also modulate NK cell anti-tumor responses. We report here that presence of platelets causes coating of tumor cells, and this markedly reduces NK cell lysis of tumor cells. This is mediated by conferment of “pseudoexpression” of platelet-expressed immunoregulatory molecules to tumor cells which are absent on the tumor cells alone. Among those immunregulatory molecules we identified various ligands for NK cell receptors like MHC class I, GITR ligand or CD62P. To establish the functional significance of tumor cell pseudoexpression of platelet molecules we employed functional analyses of tumor cells and NK cells with or without coating by autologous platelets. The impaired anti-tumor reactivity of NK cells against coated tumor cells was restored by blocking MHC class I on the coating platelets, while isotype control had no effect. Moreover, coating of tumor cells by platelets was validated by ex vivo analyses of primary leukemic cells from patients which also revealed substantial coating by platelets and confered expression of NK cell-modulating molecules. Our data indicate that platelets enable a molecular mimicry of tumor cells, which enables tumor cells to escape NK cell-mediated tumor immunosurveillance. Disclosures: No relevant conflicts of interest to declare.

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