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1.
Blood ; 123(5): 678-86, 2014 Jan 30.
Article in English | MEDLINE | ID: mdl-24326534

ABSTRACT

Natural killer (NK) cells mediate antilymphoma activity by spontaneous cytotoxicity and antibody-dependent cell-mediated cytotoxicity (ADCC) when triggered by rituximab, an anti-CD20 monoclonal antibody (mAb) used to treat patients with B-cell lymphomas. The balance of inhibitory and activating signals determines the magnitude of the efficacy of NK cells by spontaneous cytotoxicity. Here, using a killer-cell immunoglobulin-like receptor (KIR) transgenic murine model, we show that blockade of the interface of inhibitory KIRs with major histocompatibility complex (MHC) class I antigens on lymphoma cells by anti-KIR antibodies prevents a tolerogenic interaction and augments NK-cell spontaneous cytotoxicity. In combination with anti-CD20 mAbs, anti-KIR treatment induces enhanced NK-cell-mediated, rituximab-dependent cytotoxicity against lymphoma in vitro and in vivo in KIR transgenic and syngeneic murine lymphoma models. These results support a therapeutic strategy of combination rituximab and KIR blockade through lirilumab, illustrating the potential efficacy of combining a tumor-targeting therapy with an NK-cell agonist, thus stimulating the postrituximab antilymphoma immune response.


Subject(s)
Antibodies, Monoclonal, Murine-Derived/therapeutic use , Antibodies, Monoclonal/therapeutic use , Antigens, CD20/immunology , Killer Cells, Natural/immunology , Lymphoma/therapy , Receptors, KIR/immunology , Animals , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal, Murine-Derived/immunology , Antibody-Dependent Cell Cytotoxicity , Cell Line , Female , Histocompatibility Antigens Class I/immunology , Humans , Lymphoma/immunology , Male , Mice , Rituximab
2.
Proc Natl Acad Sci U S A ; 106(31): 12879-84, 2009 Aug 04.
Article in English | MEDLINE | ID: mdl-19561305

ABSTRACT

Natural killer (NK) cells are lymphocytes of the innate immune system able to recognize and kill tumors lacking self-MHC class I molecules. This "missing-self" recognition is mediated by the lack of engagement of MHC class I-specific inhibitory NK cell receptors that include the killer cell Ig-like receptors (KIR) in humans and Ly49 molecules in mice. A promising immunotherapeutic strategy against MHC class I(+) cancer cells is to block NK cell inhibitory receptors using monoclonal antibodies (mAb). However, interactions between MHC class I molecules and their inhibitory receptors are also required for the acquisition of NK cell functional competence, a process referred as to "education." In addition, inhibitory receptors are involved in self-tolerance on educated NK cells. Here, we developed a preclinical mouse model in which all NK cells are educated by a single transgenic inhibitory receptor, human KIR2DL3, through the engagement with its HLA-Cw3 ligand. This approach revealed that NK cells could be reprogrammed to control the development of mouse syngenic tumors in vivo. Moreover, in vivo anti-KIR mAb treatment induced the killing of HLA(+) target cells without breaking self-tolerance. Finally, the long-term infusion of anti-KIR mAb neither abolished NK cell education nor tumor cell recognition. Therefore, these results strongly support the use of inhibitory receptor blockade in cancer patients.


Subject(s)
Antibodies, Monoclonal/therapeutic use , HLA-C Antigens/physiology , Killer Cells, Natural/immunology , Neoplasms, Experimental/therapy , Receptors, KIR2DL3/physiology , Self Tolerance , Animals , Cell Line , Humans , Immunity, Innate , Mice , Mice, Inbred C57BL , Neoplasms, Experimental/immunology , Receptors, KIR2DL3/immunology
3.
Blood ; 113(22): 5488-96, 2009 May 28.
Article in English | MEDLINE | ID: mdl-19234143

ABSTRACT

Surface density of CD27 and CD11b subdivides mouse natural killer (NK) cells into 4 subsets: CD11b(low)CD27(low), CD11b(low)CD27(high), CD11b(high)CD27(high), and CD11b(high)CD27(low). To determine the developmental relationship between these 4 subsets, we used several complementary approaches. First, we took advantage of NDE transgenic mice that express enhanced green fluorescent protein (EGFP) and diphtheria toxin receptor specifically in NK cells. Diphtheria toxin injection leads to a transient depletion of NK cells, allowing the monitoring of the phenotype of developing EGFP+ NK cells after diphtheria toxin injection. Second, we evaluated the overall proximity between NK-cell subsets based on their global gene profile. Third, we compared the proliferative capacity of NK-cell subsets at steady state or during replenishment of the NK-cell pool. Fourth, we performed adoptive transfers of EGFP+ NK cell subsets from NDE mice into unirradiated mice and followed the fate of transferred cells. The results of these various experiments collectively support a 4-stage model of NK-cell maturation CD11b(low)CD27(low) --> CD11b(low)CD27(high) --> CD11b(high)CD27(high) --> CD11b(high)CD27(low). This developmental program appears to be associated with a progressive acquisition of NK-cell effector functions.


Subject(s)
Cell Differentiation/physiology , Killer Cells, Natural/physiology , Animals , CD11b Antigen/metabolism , Cell Differentiation/drug effects , Cell Differentiation/genetics , Cells, Cultured , Diphtheria Toxin/immunology , Diphtheria Toxin/pharmacology , Gene Expression Profiling , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Killer Cells, Natural/drug effects , Killer Cells, Natural/metabolism , Lymphocyte Activation/drug effects , Lymphocyte Activation/genetics , Lymphocyte Activation/immunology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Oligonucleotide Array Sequence Analysis , Time Factors , Tumor Necrosis Factor Receptor Superfamily, Member 7/metabolism
4.
J Immunol ; 181(3): 1627-31, 2008 Aug 01.
Article in English | MEDLINE | ID: mdl-18641298

ABSTRACT

Recent evidence suggests that NK cells require priming to display full effector activity. In this study, we demonstrate that IL-18 contributed to this phenomenon. IL-18 signaling-deficient NK cells were found to be unable to secrete IFN-gamma in response to ex vivo stimulation with IL-12. This was not due to a costimulatory role of IL-18, because blocking IL-18 signaling during the ex vivo stimulation with IL-12 did not alter IFN-gamma production by wild-type NK cells. Rather, we demonstrate that IL-18 primes NK cells in vivo to produce IFN-gamma upon subsequent stimulation with IL-12. Importantly, IL-12-induced IFN-gamma transcription by NK cells was comparable in IL-18 signaling-deficient and -sufficient NK cells. This suggests that priming by IL-18 leads to an improved translation of IFN-gamma mRNA. These results reveal a novel type of cooperation between IL-12 and IL-18 that requires the sequential action of these cytokines.


Subject(s)
Cross-Priming/immunology , Interleukin-18/immunology , Interleukin-18/metabolism , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Animals , Cells, Cultured , Interferon-gamma/biosynthesis , Interleukin-12/pharmacology , Interleukin-18/deficiency , Interleukin-18/genetics , Killer Cells, Natural/drug effects , Mice , Mice, Inbred C57BL , Mice, Knockout , Myeloid Differentiation Factor 88/deficiency , Myeloid Differentiation Factor 88/genetics , Myeloid Differentiation Factor 88/metabolism , Signal Transduction/drug effects
5.
Proc Natl Acad Sci U S A ; 104(9): 3384-9, 2007 Feb 27.
Article in English | MEDLINE | ID: mdl-17360655

ABSTRACT

Natural killer (NK) cells contribute to a variety of innate immune responses to viruses, tumors and allogeneic cells. However, our understanding of NK cell biology is severely limited by the lack of consensus phenotypic definition of these cells across species, by the lack of specific marker to visualize them in situ, and by the lack of a genetic model where NK cells may be selectively ablated. NKp46/CD335 is an Ig-like superfamily cell surface receptor involved in human NK cell activation. In addition to human, we show here that NKp46 is expressed by NK cells in all mouse strains analyzed, as well as in three common monkey species, prompting a unifying phenotypic definition of NK cells across species based on NKp46 cell surface expression. Mouse NKp46 triggers NK cell effector function and allows the detection of NK cells in situ. NKp46 expression parallels cell engagement into NK differentiation programs because it is detected on all NK cells from the immature CD122(+)NK1.1(+)DX5(-) stage and on a minute fraction of NK-like T cells, but not on CD1d-restricted NKT cells. Moreover, human NKp46 promoter drives NK cell selective expression both in vitro and in vivo. Using NKp46 promoter, we generated transgenic mice expressing EGFP and the diphtheria toxin (DT) receptor in NK cells. DT injection in these mice leads to a complete and selective NK cell ablation. This model paves a way for the in vivo characterization and preclinical assessment of NK cell biological function.


Subject(s)
Gene Expression Regulation/immunology , Killer Cells, Natural/cytology , Membrane Glycoproteins/metabolism , Receptors, Immunologic/metabolism , Animals , Antigens, Ly , Cell Differentiation/immunology , Diphtheria Toxin/toxicity , Flow Cytometry , Green Fluorescent Proteins/metabolism , Haplorhini , Immunophenotyping , Killer Cells, Natural/drug effects , Killer Cells, Natural/metabolism , Membrane Glycoproteins/genetics , Mice , Mice, Transgenic , Microscopy, Fluorescence , Natural Cytotoxicity Triggering Receptor 1 , Promoter Regions, Genetic/genetics , Receptors, Immunologic/genetics
6.
Blood ; 107(6): 2364-72, 2006 Mar 15.
Article in English | MEDLINE | ID: mdl-16291591

ABSTRACT

Natural killer (NK) cells express an array of activating receptors that associate with DAP12 (KARAP), CD3zeta, and/or FcRgamma ITAM (immunoreceptor tyrosine-based activation motif)-bearing signaling subunits. In T and mast cells, ITAM-dependent signals are integrated by critical scaffolding elements such as LAT (linker for activation of T cells) and NTAL (non-T-cell activation linker). Using mice that are deficient for ITAM-bearing molecules, LAT or NTAL, we show that NK cell cytotoxicity and interferon-gamma secretion are initiated by ITAM-dependent and -independent as well as LAT/NTAL-dependent and -independent pathways. The role of these various signaling circuits depends on the target cell as well as on the activation status of the NK cell. The multiplicity and the plasticity of the pathways that initiate NK cell effector functions contrast with the situation in T cells and B cells and provide an explanation for the resiliency of NK cell effector functions to various pharmacologic inhibitors and genetic mutations in signaling molecules.


Subject(s)
Killer Cells, Natural/metabolism , Signal Transduction , Adaptor Proteins, Signal Transducing , Animals , Cytotoxicity, Immunologic , Interferon-gamma/metabolism , Killer Cells, Natural/physiology , Membrane Proteins , Mice , Phosphoproteins , Protein Structure, Tertiary
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