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1.
Clin Immunol ; 135(1): 26-32, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20093094

ABSTRACT

Killer Ig-like receptors (KIRs) are MHC class I-specific receptors expressed by Natural Killer (NK) and T cell subsets. KIRs either inhibit (KIR-L) or activate (KIR-S) lymphocyte functions. Inhibitory KIR2DL1 and activating KIR2DS1 share ligand specificity for the HLA-C2 group, consistent with their almost identical extracytoplasmic domain. This homology hampered the distinction between KIR2DL1 and KIR2DS1. We report here the characterization of the KIR2DS1(+) subsets among primary human NK and T cells. Regardless of the host HLA-C genotype, around 10% of circulating NK cells expressed KIR2DS1 in absence of KIR2DL1. In HLA-C2 individuals, KIR2DS1 was not able to induce NK cell education (i.e., the acquisition of NK cell competence) nor to interfere with KIR2DL1-induced NK cell education. KIR2DS1 was also present on rare oligoclonal TCRalphabeta(+)CD8alpha(+) and TCRalphabeta(+)CD4(-)CD8(-) subsets. As KIR2DS1 has been associated with autoimmunity and hematopoietic stem cell transplantation, these results pave the way to dissect the function of KIR2DS1 in these clinical conditions.


Subject(s)
HLA-C Antigens/immunology , Killer Cells, Natural/immunology , Receptors, KIR/biosynthesis , T-Lymphocytes/immunology , Animals , Cell Line , DNA/chemistry , DNA/genetics , Flow Cytometry , Genotype , Humans , Leukocytes, Mononuclear/immunology , Lymphocyte Activation/immunology , Mice , Receptors, KIR/genetics , Receptors, KIR/immunology
2.
Blood ; 114(13): 2667-77, 2009 Sep 24.
Article in English | MEDLINE | ID: mdl-19553639

ABSTRACT

Inhibitory-cell killer immunoglobulin-like receptors (KIR) negatively regulate natural killer (NK) cell-mediated killing of HLA class I-expressing tumors. Lack of KIR-HLA class I interactions has been associated with potent NK-mediated antitumor efficacy and increased survival in acute myeloid leukemia (AML) patients upon haploidentical stem cell transplantation from KIR-mismatched donors. To exploit this pathway pharmacologically, we generated a fully human monoclonal antibody, 1-7F9, which cross-reacts with KIR2DL1, -2, and -3 receptors, and prevents their inhibitory signaling. The 1-7F9 monoclonal antibody augmented NK cell-mediated lysis of HLA-C-expressing tumor cells, including autologous AML blasts, but did not induce killing of normal peripheral blood mononuclear cells, suggesting a therapeutic window for preferential enhancement of NK-cell cytotoxicity against malignant target cells. Administration of 1-7F9 to KIR2DL3-transgenic mice resulted in dose-dependent rejection of HLA-Cw3-positive target cells. In an immunodeficient mouse model in which inoculation of human NK cells alone was unable to protect against lethal, autologous AML, preadministration of 1-7F9 resulted in long-term survival. These data show that 1-7F9 confers specific, stable blockade of KIR, boosting NK-mediated killing of HLA-matched AML blasts in vitro and in vivo, providing a preclinical basis for initiating phase 1 clinical trials with this candidate therapeutic antibody.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Killer Cells, Natural/drug effects , Neoplasms/therapy , Receptors, KIR/immunology , Animals , Antibodies, Monoclonal/pharmacology , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cells, Cultured , Cytotoxicity, Immunologic/drug effects , Humans , Immunotherapy/methods , Killer Cells, Natural/immunology , Mice , Mice, Inbred C57BL , Mice, Inbred NOD , Mice, SCID , Mice, Transgenic , Neoplasms/immunology , Neoplasms/pathology , Receptors, KIR/antagonists & inhibitors , Receptors, KIR2DL1/chemistry , Receptors, KIR2DL1/genetics , Receptors, KIR2DL1/immunology , Receptors, KIR2DL2/chemistry , Receptors, KIR2DL2/genetics , Receptors, KIR2DL2/immunology , Receptors, KIR2DL3/genetics , Receptors, KIR2DL3/immunology , Up-Regulation/drug effects , Up-Regulation/immunology
3.
Methods Mol Biol ; 415: 291-300, 2008.
Article in English | MEDLINE | ID: mdl-18370161

ABSTRACT

Natural killer (NK) cells are major actors of innate immune responses against viruses, bacteria, parasites, and other mediators of pathology such as malignant transformation. These cells are also directly implicated in the link between innate and adaptive immunity, shaping T-cell responses. It is now obvious that manipulation of this lymphocyte subset could be the basis of new therapeutic approaches for cancer and/or pathogen-driven pathology. Hence, techniques enabling the phenotypic and functional analysis of patient NK cells are of major importance. In this chapter, we present an extensive immunophenotyping of patient NK cells as well as a recently described method to assess NK cell functional activity at the single-cell level.


Subject(s)
Immunophenotyping/methods , Killer Cells, Natural/cytology , Humans , Interferon-gamma/biosynthesis , Lysosomal-Associated Membrane Protein 1/immunology
4.
Immunity ; 25(2): 331-42, 2006 Aug.
Article in English | MEDLINE | ID: mdl-16901727

ABSTRACT

Natural killer (NK) cells recognize the absence of self MHC class I as a way to discriminate normal cells from cells in distress. In humans, this "missing self" recognition is ensured by inhibitory receptors such as KIR, which dampen NK cell activation upon interaction with their MHC class I ligands. We show here that NK cells lacking inhibitory KIR for self MHC class I molecules are present in human peripheral blood. These cells harbor a mature NK cell phenotype but are hyporesponsive to various stimuli, including MHC class I-deficient target cells. This response is in contrast to NK cells that express a single inhibitory KIR specific for self MHC class I, which are functionally competent when exposed to the same stimuli. These results show the involvement of KIR-MHC class I interactions in the calibration of NK cell effector capacities, suggesting its role in the subsequent "missing self" recognition.


Subject(s)
Histocompatibility Antigens Class I/immunology , Killer Cells, Natural/immunology , Receptors, Immunologic/immunology , Animals , Cell Line , Heterozygote , Humans , Mice , Phenotype , Receptors, KIR , Receptors, Natural Killer Cell
5.
J Immunol ; 173(12): 7223-9, 2004 Dec 15.
Article in English | MEDLINE | ID: mdl-15585844

ABSTRACT

MHC class I-specific inhibitory receptors are expressed by a subset of memory-phenotype CD8(+) T cells. Similar to NK cells, MHC class I-specific inhibitory receptors might subserve on T cells an important negative control that participates to the prevention of autologous damage. We analyzed here human CD8(+) T cells that express the Ig-like MHC class I-specific inhibitory receptors: killer cell Ig-like receptor (KIR) and CD85j. The cell surface expression of Ig-like inhibitory MHC class I receptors was found to correlate with an advanced stage of CD8(+) T cell maturation as evidenced by the reduced proliferative potential of KIR(+) and CD85j(+) T cells associated with their high intracytoplasmic perforin content. This concomitant regulation might represent a safety mechanism to control potentially harmful cytolytic CD8(+) T cells, by raising their activation threshold. Yet, KIR(+) and CD85j(+) T cells present distinct features. KIR(+)CD8(+) T cells are poor IFN-gamma producers upon TCR engagement. In addition, KIR are barely detectable at the surface of virus-specific T cells during the course of CMV or HIV-1 infection. By contrast, CD85j(+)CD8(+) T cells produce IFN-gamma upon TCR triggering, and represent a large fraction of virus-specific T cells. Thus, the cell surface expression of Ig-like inhibitory MHC class I receptors is associated with T cell engagement into various stages of the cytolytic differentiation pathway, and the cell surface expression of CD85j or KIR witnesses to the history of qualitatively and/or quantitatively distinct T cell activation events.


Subject(s)
Antigens, CD/biosynthesis , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Cytotoxicity, Immunologic , Histocompatibility Antigens Class I/immunology , Receptors, Immunologic/biosynthesis , Antigens, CD/blood , CD8-Positive T-Lymphocytes/virology , Cell Proliferation , Clone Cells , Cytomegalovirus Infections/immunology , Cytotoxicity Tests, Immunologic , HIV-1/immunology , Humans , Immunologic Memory , Immunophenotyping , Kidney Transplantation/adverse effects , Kidney Transplantation/immunology , Leukocyte Immunoglobulin-like Receptor B1 , Lymphocyte Activation/immunology , Male , Receptors, Antigen, T-Cell/biosynthesis , Receptors, Immunologic/blood , Receptors, KIR
6.
J Immunol ; 173(6): 3773-82, 2004 Sep 15.
Article in English | MEDLINE | ID: mdl-15356124

ABSTRACT

MHC class I-specific Ly49 inhibitory receptors regulate NK cell activation, thereby preventing autologous damage to normal cells. Ly49 receptors are also expressed on a subset of CD8+ T cells whose origin and function remain unknown. We report here that, despite their phenotypic and cytolytic similarities, Ly49+CD8+ T cells and conventional Ly49-CD44high memory-phenotype CD8+ T cells present strikingly distinct features. First, under steady state conditions Ly49+CD8+ T cells are poor cytokine producers (TNF-alpha and IFN-gamma) upon TCR triggering. Second, Ly49+CD8+ T cells are not induced upon various settings of Ag immunization or microbial challenge. However, Ly49 can be induced on a fraction of self-specific CD8+ T cells if CD4+ T cells are present. Finally, the size of the Ly49+CD8+ T cell subset is selectively reduced in the absence of STAT1. These results indicate that Ly49 expression is associated with a differentiation program of cytolytic CD8+ T cells triggered upon chronic antigenic exposure. They further suggest that the size of the Ly49+CD8+ T cell subset marks a history of CD8+ T cell activation that might preferentially result from endogenous inducers of inflammation rather than from microbial infections.


Subject(s)
Antigens, Ly/biosynthesis , Epitopes, T-Lymphocyte/biosynthesis , Histocompatibility Antigens Class I/immunology , Lymphocyte Activation/immunology , T-Lymphocytes, Cytotoxic/immunology , T-Lymphocytes, Cytotoxic/metabolism , Animals , Antigens, Ly/physiology , Bystander Effect/immunology , Cell Differentiation/immunology , Clone Cells , Cytotoxicity, Immunologic , Epitopes, T-Lymphocyte/physiology , Female , Lectins, C-Type , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Receptors, Antigen, T-Cell/physiology , Receptors, NK Cell Lectin-Like , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocytes, Cytotoxic/cytology , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism
7.
Eur J Immunol ; 34(4): 961-71, 2004 Apr.
Article in English | MEDLINE | ID: mdl-15048706

ABSTRACT

NKG2D and natural cytotoxicity receptors (NCR) are essential recognition structures that mediate NK cell activation. NKG2D and NCR signaling is achieved through membrane association with signaling adaptors. The adaptors that associate with NCR--such as CD3 zeta, FcR gamma and KARAP/DAP12--bear intracytoplasmic immunoreceptor tyrosine-based activation motifs that activate Syk protein tyrosine kinases. Human NKG2D associates with the DAP10 transmembrane adaptor, which bears a YxxM motif and activates the phosphatidylinositol 3-kinase pathway. In the mouse, a short NKG2D-S isoform, generated by Nkg2d alternative splicing, can associate with either DAP10 or KARAP/DAP12. Here, we report that neither short human NKG2D alternative transcripts nor NKG2D association with KARAP/DAP12 was detected in activated human NK cells. Despite these results, NK cell triggering by both recombinant soluble NKG2D ligands (MICA and ULBP-1) and anti-NCR cross-linking antibodies induced similar CD25 expression, NK cell proliferation and cytokine production. In contrast, NKG2D triggering by anti-NKG2D antibodies did not lead to any detectable activation signals. These data thus show that target recognition via NKG2D or NCR triggers all aspects of NK activation, and pave the way for further dissection of the signaling pathways induced by NK cell recognition of ULBP-1 and MICA.


Subject(s)
Killer Cells, Natural/immunology , Lymphocyte Activation/immunology , Lymphocyte Subsets/immunology , Receptors, Immunologic , Receptors, Immunologic/immunology , Signal Transduction/immunology , Adaptor Proteins, Signal Transducing , Amino Acid Sequence , Animals , Flow Cytometry , Humans , Membrane Proteins/immunology , Mice , Molecular Sequence Data , NK Cell Lectin-Like Receptor Subfamily K , Receptors, Immunologic/genetics , Receptors, Natural Killer Cell , Reverse Transcriptase Polymerase Chain Reaction
9.
Eur J Immunol ; 33(12): 3514-22, 2003 Dec.
Article in English | MEDLINE | ID: mdl-14635062

ABSTRACT

A common feature of hematopoietic activating immunoreceptors resides in their association at the cell surface with transmembrane signaling adaptors. Several adaptors, such as the CD3 molecules, FcRgamma and KARAP/DAP12, harbor intracytoplasmic immunoreceptor tyrosine-based activation motifs (ITAM) that activate Syk-family protein tyrosine kinases. In contrast, another transmembrane adaptor, DAP10, bears a YxxM motif that delivers signals by activation of lipid kinase pathways. We show here that the human signal-regulatory protein SIRPbeta1 can associate with both DAP10 and KARAP/DAP12 in a model of RBL-2H3 cell transfectants. In association with KARAP/DAP12, SIRPbeta1 complexes are capable of inducing serotonin release and tumor necrosis factor (TNF) secretion. By contrast,in the absence of KARAP/DAP12, engagement of SIRPbeta1:DAP10 complexes does not lead to detectable serotonin release or TNF secretion by RBL-2H3 transfectants. However, triggering of SIRPbeta1:DAP10 complexes co-stimulates RBL-2H3 effector function induced by sub-optimal stimulation of the endogenous FcepsilonRI complex. Therefore, we report here a cellular model in which the association of a cell surface receptor with various signaling adaptors dictates the co-stimulatory or the direct stimulatory properties of the complex.


Subject(s)
Antigens, Differentiation , Membrane Proteins/physiology , Receptors, Immunologic/physiology , Adaptor Proteins, Signal Transducing , Animals , Cell Line, Tumor , Dimerization , Humans , Mast Cells/metabolism , Membrane Glycoproteins/metabolism , Membrane Proteins/metabolism , Neural Cell Adhesion Molecule L1/metabolism , Rats , Receptors, Antigen, T-Cell/metabolism , Receptors, Antigen, T-Cell/physiology , Receptors, Cell Surface , Receptors, IgG/metabolism , Receptors, KIR , Transfection
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