Maternal adaptation to vasculogenesis and angiogenesis at the feto-maternal interface.
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Adaptation, Physiological↗
Biomedical subjects
O Mandelboim
Publications and source records attributed to O Mandelboim.
Murine B-cell leukemia lymphoma (BCL1) cells as a target for NK cell-mediated immunotherapy.
Natural killer (NK) cells are important for their ability to recognize and lyse tumor cells and virus infected cells. NK cells express triggering receptors that are specific for non-MHC ligands. This article describes the 35S release cytotoxic assay, which measures the ability of NK cells derived from spleen cells taken from polyIC-treated mice to lyse B-cell leukemia (BCL1) cells. BCL1 cells express ligands for NKp46 on the cell surface membrane and they are sensitive to allogeneic but not syngeneic IL-2 activated natural killer cells.
Animals↗
Recognition of HLA-Cw4 but not HLA-Cw6 by the NK cell receptor killer cell Ig-like receptor two-domain short tail number 4.
NK cells are cytotoxic to virus-infected and tumor cells that have lost surface expression of class I MHC proteins. Target cell expression of class I MHC proteins inhibits NK cytotoxicity through binding to inhibitory NK receptors. In contrast, a similar family of activating NK receptors, characterized by the presence of a charged residue in their transmembrane portion and a truncated cytoplasmic tail, augment lysis by NK cells when ligated by an appropriate class I MHC protein. However, the class I MHC specificity of many of these activating NK receptors is still unknown. Here, we show enhanced lysis of HLA-Cw4 but not HLA-Cw6-expressing cells, by a subset of NK clones. This subset may express killer cell Ig-like receptor two-domain short tail number 4 (KIR2DS4), as suggested by staining with various mAb. It is still possible, however, that these clones may express receptors other than KIR2DS4 that might recognize HLA-Cw4. Binding of KIR2DS4-Ig fusion protein to cells expressing HLA-Cw4 but not to those expressing HLA-Cw6 was also observed. The binding of KIR2DS4-Ig to HLA-Cw4 is weaker than that of killer cell Ig-like receptor two-domain long tail number 1 (KIR2DL1)-Ig fusion protein; however, such weak recognition is capable of inhibiting lysis by an NK transfectant expressing a chimeric molecule of KIR2DS4 fused to the transmembrane and cytoplasmic portion of KIR2DL1. Residue alpha14 is shown to be important in the KIR2DS4 binding to HLA-Cw4. Implications of the role of the activating NK receptors in immunosurveillance are discussed.
Adjuvants, Immunologic↗
Recognition of haemagglutinins on virus-infected cells by NKp46 activates lysis by human NK cells.
Natural killer (NK) cells destroy virus-infected and tumour cells, apparently without the need for previous antigen stimulation. In part, target cells are recognized by their diminished expression of major histocompatibility complex (MHC) class I molecules, which normally interact with inhibitory receptors on the NK cell surface. NK cells also express triggering receptors that are specific for non-MHC ligands; but the nature of the ligands recognized on target cells is undefined. NKp46 is thought to be the main activating receptor for human NK cells. Here we show that a soluble NKp46-immunoglobulin fusion protein binds to both the haemagglutinin of influenza virus and the haemagglutinin-neuraminidase of parainfluenza virus. In a substantial subset of NK cells, recognition by NKp46 is required to lyse cells expressing the corresponding viral glycoproteins. The binding requires the sialylation of NKp46 oligosaccharides, which is consistent with the known sialic binding capacity of the viral glycoproteins. These findings indicate how NKp46-expressing NK cells may recognize target cells infected by influenza or parainfluenza without the decreased expression of target-cell MHC class I protein.
Animals↗
Recognition of viral hemagglutinins by NKp44 but not by NKp30.
Natural killer (NK) cells destroy virus-infected and tumor cells without prior antigen stimulation. The NK cell cytotoxicity is regulated in large part by the expression of NK cell receptors that are able to bind major histocompatibility complex (MHC) class I glycoproteins. NK cells also express lysis triggering receptors specific for non-MHC ligands, including NKp30, NKp44, NKp46 and CD16. However, the nature of their ligands, recognized on target cells, is undefined. We have recently shown that the NKp46 protein, but not the CD16 protein, recognizes the hemagglutinin (HA) of influenza virus (IV) and the hemagglutinin-neuraminidase (HN) of Sendai virus (SV), and that the recognition of HA from IV requires the sialylation of NKp46 oligosaccharides. We have also demonstrated that binding of NKp46 to HA of IV is required for lysis of cells expressing the corresponding glycoproteins by a substantial subset of NK clones. Here we show that NKp44, but not NKp30, can also recognize the HA of both IV and SV and that the recognition of IV HA requires the sialylation of the NKp44 receptor in a similar way to that of NKp46. SV infection of 721.221 cells expressing MHC class I proteinsresulted in the abrogation of the inhibition by NK clones expressing high levels of NKp44. In addition, the binding of NKp44 to HA improves the ability of some NK clones to lyse IV infected cells.
Antibodies, Viral↗
NKp46.
Combating diseases such as cancer and virus infection is one of the major goals of the next millennium. Remarkably, our immune system has developed a unique cell type called Natural Killer (NK) cells, able to kill cancer and virus-infected cells. The nature of the lysis/killer receptors expressed on NK cells, mediating this killing, and their ligands, is only little understood. Four lysis receptors for human NK cells were recently identified, including the NKp30, NKp44, NKp46 and CD16, all of which are capable of mediating direct killing of virus-infected and tumor cells. Among these, the NKp46 receptor is considered to be the major lysis receptor for NK cells. The viral hemagglutinin protein was recently identified as the ligand for the NKp46 receptor. However, the cellular (non-viral) ligands recognized by all of the lysis receptors (NKp30, NKp44, NKp46 and CD16) are currently unknown.
Animals↗
The role of NK cells in innate immunity.
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Cytotoxicity, Immunologic↗
N-linked carbohydrate on human leukocyte antigen-C and recognition by natural killer cell inhibitory receptors.
The possible role of carbohydrate in the interaction of HLA-C with a human inhibitory natural Killer cell Immunoglobulin-like Receptor with two Ig domains, KIR2DL1, was investigated. Transfectants of 721.221 (a class I MHC-negative human B cell line) expressing only HLA-Cw4 or -Cw6 or their respective non-glycosylated mutants (N86Q, S88A) were made. The binding of a KIR2DL1-Ig fusion protein to the non-glycosylated mutant HLA-Cw4- or -Cw6-expressing cells was markedly decreased compared to the wild type-expressing cells. The ability to induce an inhibitory signal in the NK tumor line YTS transfected with KIR2DL1 was also impaired in the nonglycosylated mutant expressing cells. Furthermore, in a second functional assay, mutant HLA-Cw4 and -Cw6 molecules had impaired ability to induce signal transduction in BW cells expressing a KIR2DL1-CD3 zeta chain chimeric protein. Thus, the deletion of the N-linked glycosylation signal in HLA-Cw4 and -Cw6 greatly reduced recognition by KIR2DL1. Alternative interpretations of the data are discussed.
Amino Acid Substitution↗
The human natural killer cell immune synapse.
Inhibitory killer Ig-like receptors (KIR) at the surface of natural killer (NK) cells induced clustering of HLA-C at the contacting surface of target cells. In this manner, inhibitory immune synapses were formed as human NK cells surveyed target cells. At target/NK cell synapses, HLA-C/KIR distributed into rings around central patches of intercellular adhesion molecule-1/lymphocyte function-associated antigen-1, the opposite orientation to mature murine T cell-activating synapses. This organization of protein was stable for at least 20 min. Cells could support multiple synapses simultaneously, and clusters of HLA-C moved as NK cells crawled over target cells. Clustering required a divalent metal cation, explaining how metal chelators inhibit KIR function. Surprisingly, however, formation of inhibitory synapses was unaffected by ATP depletion and the cytoskeletal inhibitors, colchicine and cytochalsins B and D. Clearly, supramolecular organization within plasma membranes is critical for NK cell immunosurveillance.
Actins↗
Human CD16 as a lysis receptor mediating direct natural killer cell cytotoxicity.
In addition to their role in peptide antigen presentation, class I MHC proteins also play a critical role in inhibiting natural killer (NK) cytotoxicity through interaction with NK inhibitory receptors. Thus, NK cells are cytotoxic to virus-infected and tumor cells that have lost class I MHC protein expression. However, the nature of the receptors involved in the triggering of lysis of target cells is poorly understood. CD16 (Fcgamma receptor III) has been described as a receptor expressed on NK cells that facilitates antibody-dependent cellular cytotoxicity (ADCC) by binding to the Fc portion of various antibodies. However, we show here that CD16 has a broader function and is directly involved in the lysis of some virus-infected cells and tumor cells, independent of antibody binding. The presence of a putative CD16 ligand on appropriate target cells has also been demonstrated by the use of a CD16-Ig fusion protein.
Antibodies, Monoclonal↗
The transmembrane sequence of human histocompatibility leukocyte antigen (HLA)-C as a determinant in inhibition of a subset of natural killer cells.
Molecular interactions with the extracellular domains of class I major histocompatibility complex proteins are major determinants of immune recognition that have been extensively studied both physically and biochemically. However, no immunological function has yet been placed on the transmembrane or cytoplasmic amino acid sequences of these proteins despite strict conservation of unique features within each class I major histocompatibility complex locus. Here we report that lysis by a subset of natural killer (NK) cells inhibited by target cell expression of human histocompatibility leukocyte antigen (HLA)-Cw6 or -Cw7 was not inhibited by expression of chimeric proteins consisting of the extracellular domains of HLA-C and the COOH-terminal portion of HLA-G. Assays using transfectants expressing a variety of HLA-Cw6 mutants identified the transmembrane sequence and, in particular, cysteine at position 309 as necessary for inhibition of 68% (25/37) of NK cell lines and 23% (33/145) of NK clones tested. Moreover, these NK clones inhibited by target cell expression of HLA-Cw6 and dependent upon the transmembrane sequence were found not to express or to only dimly express NK inhibitory receptors (NKIR1) that are EB6/HP3E4-positive. Furthermore, assays using monoclonal antibody blocking suggest that an NK receptor other than NKIR1 or CD94 is responsible for recognition dependent upon the transmembrane sequence of HLA-Cw6.
Amino Acid Sequence↗
Human leucocyte antigen-G and its recognition by natural killer cells.
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Animals↗
The selective downregulation of class I major histocompatibility complex proteins by HIV-1 protects HIV-infected cells from NK cells.
To avoid detection by CTL, HIV encodes mechanisms for removal of class I MHC proteins from the surface of infected cells. However, class I downregulation potentially exposes the virus-infected cell to attack by NK cells. Human lymphoid cells are protected from NK cell cytotoxicity primarily by HLA-C and HLA-E. We present evidence that HIV-1 selectively downregulates HLA-A and HLA-B but does not significantly affect HLA-C or HLA-E. We then identify the residues in HLA-C and HLA-E that protect them from HIV down-regulation. This selective downregulation allows HIV-infected cells to avoid NK cell-mediated lysis and may represent for HIV a balance between escape from CTL and maintenance of protection from NK cells. These results suggest that subpopulations of CTL and NK cells may be uniquely suited for combating HIV.
Cells, Cultured↗
Natural killer activating receptors trigger interferon gamma secretion from T cells and natural killer cells.
Proliferation of human CD4+ alphabeta T cells expressing a natural killer cell activating receptor (NKAR) has been shown to be enhanced, particularly in response to low doses of antigen, if the target cells present appropriate human class I major histocompatibility complex (MHC) molecules. Here, we show that NKAR also enhance proliferation and killing of target cells by subsets of CD8+ alphabeta and CD8+ gammadelta T cells, as well as by NK cells. Strikingly, interferon gamma secretion from all of these types of lymphocytes was markedly increased by interaction of the NKAR with their MHC class I ligands, independently of enhancement of proliferation. Thus, the recognition of class I MHC molecules by NKAR on both T cells and NK cells may provide a regulatory mechanism that affects immune responses through the secretion of interferon gamma and possibly other cytokines. It represents a signal for cytokine secretion alternative and/or augmentative to that through the T cell receptor.
CD56 Antigen↗
Multiple receptors for HLA-G on human natural killer cells.
HLA-G is the putative natural killer (NK) cell inhibitory ligand expressed on the extravillous cytotrophoblast of the human placenta. Killing of the class I negative human B cell line 721.221 by NK cells is inhibited by the expression of HLA-G. This inhibition is dependent on a high level of HLA-G expression. In the present study, the nature of the receptors that mediate the inhibition has been studied with 140 NK cell lines from two donors and 246 NK clones from 5 donors by blocking the inhibition using monoclonal antibodies against the known NK inhibitory receptors: CD158a, CD158b, and CD94. Both CD94 and the two CD158 proteins can function as receptors, although the former clearly predominates. In many cases, a combination of antibodies to these receptors is required to achieve maximal reversal of inhibition. Moreover, in at least one-third of the NK cells that are inhibited by HLA-G, these antibodies alone or in combination do not reverse inhibition, strongly suggesting the existence of a third major unidentified receptor for HLA-G.
Antigens, CD↗
Identification of shared tumor-associated antigen peptides between two spontaneous lung carcinomas.
CTLs recognize antigenic peptides bound to MHC class I Ags on the cell surface of tumor cells. Tumor-associated Ag (TAA) peptides are 8 to 10 amino acids long and can be derived from normal, mutated, or viral proteins. The majority of T cell-defined Ags have been identified in human melanoma cells. These were shown to be commonly expressed by different allogeneic melanomas that share the same MHC molecule. We have recently isolated Kb-restricted TAA peptides, which are mutations of the gap junction protein connexin 37, from the spontaneous C57BL/6 Lewis lung carcinoma (3LL). These peptides, named MUT 1 and MUT 2, serve as CTL epitopes and can induce CTL activity in vivo. Using CTL cross-reaction assays, peptide extraction, HPLC fractionation, and reverse transcriptase-PCR amplification, we show that clones of another spontaneous C57BL/6 lung carcinoma, CMT 64, share TAA peptides with the 3LL carcinoma. Vaccination with synthetic MUT 1 or MUT 2 induces CTLs that efficiently lyse CMT 64-derived clones, protects mice from CMT 64 metastasis, and affords therapy of established CMT 64 metastases. Hence, shared CTL epitopes exist between two spontaneous murine lung carcinomas.
Animals↗
Correction. CTL induction by a tumour-associated antigen octapeptide derived from a murine lung carcinoma.
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Animals↗
Natural killer cell lines kill autologous beta2-microglobulin-deficient melanoma cells: implications for cancer immunotherapy.
Cancer vaccines used to generate specific cytotoxic T lymphocytes are not effective against tumor cells that have lost or suppressed expression of their class I major histocompatibility complex proteins. This loss is common in some cancers and particularly in metastatic lesions. We show that beta2-microglobulin-deficient class I-negative melanoma variants derived from patients undergoing specific T cell therapy are lysed by heterologous as well as autologous natural killer (NK) lines and clones, but not by specific T cells. Moreover, the minor NK cell fraction but not the major T cell fraction derived from heterologous lymphokine activated killer cells kills those tumor cell lines. ICAM-1 expression by the different class I protein deficient tumors was correlated with their sensitivity to lysis by NK cells. Adoptive autologous NK therapy may be an important supplement to consider in the design of new cancer immunotherapies.
Cancer Vaccines↗