scholarly journals Interferon gamma production by natural killer (NK) cells and NK1.1+ T cells upon NKR-P1 cross-linking.

1996 ◽  
Vol 183 (5) ◽  
pp. 2391-2396 ◽  
Author(s):  
H Arase ◽  
N Arase ◽  
T Saito
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Interferon Gamma ◽  
Nk Cell ◽  
Cell Receptor ◽  
Interleukin 4 ◽  
Cross Linking ◽  
Target Cells ◽  
Ifn Gamma

Natural killer (NK) cells play an important role in immune response by producing interferon gamma (IFN-gamma) as well as exhibiting cytotoxic function. IFN-gamma produced by NK cells has been suggested to be involved in differentiation of T helper cells. On the other hand, the NKR-P1 molecule was recently identified as one of the important NK cell receptors, and it recognizes certain kinds of oligosaccharides on target cells and triggers NK cells for cytotoxicity. In the present study, we found that NK cells produce great amounts of IFN-gamma upon cross-linking of the NKR-P1 molecule. In contrast, stimulation of NK cells with IL-2 induced proliferation without producing IFN-gamma. Similar to NK cells, NK1.1+ T cells also produced IFN-gamma upon NKR-P1 cross-linking. NK1.1+ T cells produced IFN-gamma but not interleukin 4 (IL-4) upon NKR-P1 cross-linking, whereas they secreted both IFN-gamma and IL-4 upon T cell receptor cross-linking. These results indicate that NKR-P1 is a receptor molecule on NK and NK1.1+ T cells that induces not only cytotoxicity but also IFN-gamma production. Our findings provide a new pathway for IFN-gamma production by NK and NK1.1+ T cells through NKR-P1 molecules; it may be essential for immune regulation.

scholarly journals Natural killer cells are a source of interferon gamma that drives differentiation of CD4+ T cell subsets and induces early resistance to Leishmania major in mice.

1993 ◽  
Vol 178 (2) ◽  
pp. 567-577 ◽  
Author(s):  
T M Scharton ◽  
P Scott
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Interferon Gamma ◽  
Leishmania Major ◽  
Nk Cell ◽  
T Cell Subsets ◽  
Th2 Cells ◽  
Th1 Cell ◽  
Ifn Gamma

Infection of mice with the protozoan Leishmania major provides an excellent model to define the factors involved in T helper (Th) subset development, since Th1 cells confer protection in resistant strains of mice, whereas Th2 cells are associated with the fatal outcome of susceptible mice. We previously found that interferon gamma (IFN-gamma) was required for Th1 cell development after infection of mice with L. major. In this report, we evaluate the contribution of natural killer (NK) cells to IFN-gamma levels early in L. major infection. NK cell activity was higher in resistant C3H/HeN mice than in susceptible BALB/c mice during the first week of infection, and removal of NK cells significantly decreased IFN-gamma levels and promoted interleukin 4 (IL-4) production in both the draining lymph nodes and spleen. IFN-gamma production by NK cells required the presence of CD4+ T cells or IL-2, but not CD8+ T cells. Enhanced disease, as measured by parasite numbers and lesion development, was observed in NK cell-depleted mice. Furthermore, a comparison of the NK cell response and the subsequent parasite burden in several inbred strains of mice demonstrated that NK cells mediate early resistance to L. major. Together, these data indicate that the stimulation of NK cells, through the production of IFN-gamma, plays an important role in initiating Th1 cell differentiation in leishmaniasis and in controlling early resistance to L. major.

scholarly journals Recognition of virus-infected cells by natural killer cell clones is controlled by polymorphic target cell elements.

1993 ◽  
Vol 178 (3) ◽  
pp. 961-969 ◽  
Author(s):  
M S Malnati ◽  
P Lusso ◽  
E Ciccone ◽  
A Moretta ◽  
L Moretta ◽  
...  
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Target Cell ◽  
Nk Cell ◽  
Class I ◽  
Target Cells ◽  
Cell Recognition ◽  
Infected Cells ◽  
Nk Cell Recognition

Natural killer (NK) cells provide a first line of defense against viral infections. The mechanisms by which NK cells recognize and eliminate infected cells are still largely unknown. To test whether target cell elements contribute to NK cell recognition of virus-infected cells, human NK cells were cloned from two unrelated donors and assayed for their ability to kill normal autologous or allogeneic cells before and after infection by human herpesvirus 6 (HHV-6), a T-lymphotropic herpesvirus. Of 132 NK clones isolated from donor 1, all displayed strong cytolytic activity against the NK-sensitive cell line K562, none killed uninfected autologous T cells, and 65 (49%) killed autologous T cells infected with HHV-6. A panel of representative NK clones from donors 1 and 2 was tested on targets obtained from four donors. A wide heterogeneity was observed in the specificity of lysis of infected target cells among the NK clones. Some clones killed none, some killed only one, and others killed more than one of the different HHV-6-infected target cells. Killing of infected targets was not due to complete absence of class I molecules because class I surface levels were only partially affected by HHV-6 infection. Thus, target cell recognition is not controlled by the effector NK cell alone, but also by polymorphic elements on the target cell that restrict NK cell recognition. Furthermore, NK clones from different donors display a variable range of specificities in their recognition of infected target cells.

scholarly journals Slaying the Trojan Horse: Natural Killer Cells Exhibit Robust Anti-HIV-1 Antibody-Dependent Activation and Cytolysis against Allogeneic T Cells

2014 ◽  
Vol 89 (1) ◽  
pp. 97-109 ◽  
Author(s):  
Shayarana L. Gooneratne ◽  
Jonathan Richard ◽  
Wen Shi Lee ◽  
Andrés Finzi ◽  
Stephen J. Kent ◽  
...  
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Target Cells ◽  
Dependent Manner ◽  
Inhibitory Receptors ◽  
Cell Responses ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACTMany attempts to design prophylactic human immunodeficiency virus type 1 (HIV-1) vaccines have focused on the induction of neutralizing antibodies (Abs) that block infection by free virions. Despite the focus on viral particles, virus-infected cells, which can be found within mucosal secretions, are more infectious than free virus bothin vitroandin vivo. Furthermore, assessment of human transmission couples suggests infected seminal lymphocytes might be responsible for a proportion of HIV-1 transmissions. Although vaccines that induce neutralizing Abs are sought, only some broadly neutralizing Abs efficiently block cell-to-cell transmission of HIV-1. As HIV-1 vaccines need to elicit immune responses capable of controlling both free and cell-associated virus, we evaluated the potential of natural killer (NK) cells to respond in an Ab-dependent manner to allogeneic T cells bearing HIV-1 antigens. This study presents data measuring Ab-dependent anti-HIV-1 NK cell responses to primary and transformed allogeneic T-cell targets. We found that NK cells are robustly activated in an anti-HIV-1 Ab-dependent manner against allogeneic targets and that tested target cells are subject to Ab-dependent cytolysis. Furthermore, the educated KIR3DL1+NK cell subset from HLA-Bw4+individuals exhibits an activation advantage over the KIR3DL1−subset that contains both NK cells educated through other receptor/ligand combinations and uneducated NK cells. These results are intriguing and important for understanding the regulation of Ab-dependent NK cell responses and are potentially valuable for designing Ab-dependent therapies and/or vaccines.IMPORTANCENK cell-mediated anti-HIV-1 antibody-dependent functions have been associated with protection from infection and disease progression; however, their role in protecting from infection with allogeneic cells infected with HIV-1 is unknown. We found that HIV-1-specific ADCC antibodies bound to allogeneic cells infected with HIV-1 or coated with HIV-1 gp120 were capable of activating NK cells and/or trigging cytolysis of the allogeneic target cells. This suggests ADCC may be able to assist in preventing infection with cell-associated HIV-1. In order to fully utilize NK cell-mediated Ab-dependent effector functions, it might also be important that educated NK cells, which hold the highest activation potential, can become activated against targets bearing HIV-1 antigens and expressing the ligands for self-inhibitory receptors. Here, we show that with Ab-dependent stimulation, NK cells expressing inhibitory receptors can mediate robust activation against targets expressing the ligands for those receptors.

scholarly journals Deciphering the Immunological Phenomenon of Adaptive Natural Killer (NK) Cells and Cytomegalovirus (CMV)

2020 ◽  
Vol 21 (22) ◽  
pp. 8864
Author(s):  
Samantha Barnes ◽  
Ophelia Schilizzi ◽  
Katherine M. Audsley ◽  
Hannah V. Newnes ◽  
Bree Foley
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cell Biology ◽  
Nk Cell ◽  
Cell Receptor ◽  
Vital Role ◽  
Immune Memory ◽  
Target Cells ◽  
Cytokines And Chemokines ◽  
Adaptive Immune Cells

Natural killer (NK) cells play a significant and vital role in the first line of defense against infection through their ability to target cells without prior sensitization. They also contribute significantly to the activation and recruitment of both innate and adaptive immune cells through the production of a range of cytokines and chemokines. In the context of cytomegalovirus (CMV) infection, NK cells and CMV have co-evolved side by side to employ several mechanisms to evade one another. However, during this co-evolution the discovery of a subset of long-lived NK cells with enhanced effector potential, increased antibody-dependent responses and the potential to mediate immune memory has revolutionized the field of NK cell biology. The ability of a virus to imprint on the NK cell receptor repertoire resulting in the expansion of diverse, highly functional NK cells to this day remains a significant immunological phenomenon that only occurs in the context of CMV. Here we review our current understanding of the development of these NK cells, commonly referred to as adaptive NK cells and their current role in transplantation, infection, vaccination and cancer immunotherapy to decipher the complex role of CMV in dictating NK cell functional fate.

scholarly journals Response of resting human peripheral blood natural killer cells to interleukin 2.

1984 ◽  
Vol 160 (4) ◽  
pp. 1147-1169 ◽  
Author(s):  
G Trinchieri ◽  
M Matsumoto-Kobayashi ◽  
S C Clark ◽  
J Seehra ◽  
L London ◽  
...  
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Peripheral Blood ◽  
Nk Cell ◽  
Human Peripheral Blood ◽  
Interleukin 2 ◽  
Cell Activity ◽  
Experimental Conditions ◽  
Ifn Gamma

The present study shows that recombinant interleukin 2 (IL-2) purified to homogeneity induces a rapid and potent enhancement of spontaneous cytotoxicity of human peripheral blood lymphocytes. The cells mediating cytotoxicity after 18-h treatment with IL-2 have surface markers of natural killer (NK) cells and are generated from the peripheral blood subset containing spontaneous cytotoxic cells. A parallel production of gamma interferon (IFN-gamma) is induced by recombinant IL-2 (rIL-2), and NK cells appear to be the major producer cells, whereas T cells are unable to produce IFN-gamma under these experimental conditions. However, the kinetics of the enhancement of cytotoxicity are faster than those of IFN-gamma production, and monoclonal anti-IFN-gamma antibodies do not suppress this effect, making it unlikely that the IFN-gamma produced is responsible for the enhancement. The enhancement of NK cell activity induced by rIL-2 precedes any proliferative response of the lymphocytes, which is instead observed in longer-term cultures of both NK and T cells.

scholarly journals NKB1: a natural killer cell receptor involved in the recognition of polymorphic HLA-B molecules.

1994 ◽  
Vol 180 (2) ◽  
pp. 537-543 ◽  
Author(s):  
V Litwin ◽  
J Gumperz ◽  
P Parham ◽  
J H Phillips ◽  
L L Lanier
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Cell Clone ◽  
Killer Cell ◽  
Cell Receptor ◽  
Target Cells ◽  
Multiple Alleles ◽  
Barr Virus ◽  
Cell Clones

Natural killer (NK) cells kill normal and transformed hematopoietic cells that lack expression of major histocompatibility complex (MHC) class I antigens. Lysis of HLA-negative Epstein Barr virus-transformed B lymphoblastoid cell lines (B-LCL) by human NK cell clones can be inhibited by transfection of the target cells with certain HLA-A, -B, or -C alleles. NK cell clones established from an individual demonstrate clonal heterogeneity in HLA recognition and a single NK clone can recognize multiple alleles. We describe a potential human NK cell receptor (NKB1) for certain HLA-B alleles (e.g., HLA-B*5101 and-B*5801) identified by the mAb DX9. NKB1 is a 70-kD glycoprotein that is expressed on a subset of NK cells and NK cell clones. DX9 monoclonal antibody (mAb) specifically inhibits the interaction between NK cell clones and B-LCL targets transfected with certain HLA-B alleles, but does not affect recognition of HLA-A or HLA-C antigens. An individual NK cell clone can independently recognize B-LCL targets transfected with HLA-B or HLA-C antigens; however, DX9 mAb only affects interaction with transfectants expressing certain HLA-B alleles. These findings demonstrate the existence of NK cell receptors involved in the recognition of HLA-B and imply the presence of multiple receptors for MHC on an individual NK clone.

scholarly journals Signal transduction by the CD2 antigen in T cells and natural killer cells: requirement for expression of a functional T cell receptor or binding of antibody Fc to the Fc receptor, Fc gamma RIIIA (CD16).

1991 ◽  
Vol 174 (6) ◽  
pp. 1407-1415 ◽  
Author(s):  
L L Spruyt ◽  
M J Glennie ◽  
A D Beyers ◽  
A F Williams
Keyword(s):  
Signal Transduction ◽  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
T Cell Receptor ◽  
Nk Cell ◽  
Cell Receptor ◽  
Fc Receptor ◽  
Jurkat Cells

Crosslinking of CD2 antigen on T lymphocytes and natural killer (NK) cells leads to a rise in cytoplasmic-free Ca2+ concentration ([Ca2+]i). However, CD2 seems unlikely to interact directly with the second messenger pathways since signaling via CD2 is poor in T cells that lack the T cell receptor (TCR) and is absent in L cells or insect cells that express CD2. In contrast, NK cells that are also TCR- can be triggered via CD2, but it is unclear as to whether the CD16 Fc receptor (FcR) may facilitate this effect. The CD16 transmembrane molecule is expressed in a complex with the zeta homodimer or the zeta/gamma heterodimer and these dimers are also associated with the TCR complex. Thus, it seemed that zeta chains may provide the link between signaling on NK cells and T cells. This could be tested on TCR- cells since when CD16 is transfected into T cells it is expressed in a complex with TCR zeta homodimer or the zeta/gamma heterodimer. At first, potentiation of CD2 signaling was seen on TCR- Jurkat cells expressing CD16, but this was found to be dependent on trace levels (1%) of IgG in F(ab')2 antibody preparations. With pure F(ab')2, the effect was lost. Signaling on a rat NK cell line was also re-examined with F(ab')2 antibodies that had no IgG contamination, and again no signal transduction via CD2 was seen. We thus conclude that there is no clear evidence for potent signaling via CD2 on cells that lack a TCR complex and that TCR zeta chain expressed at the cell surface is not sufficient to potentiate signaling via CD2 as measured by an increase in [Ca2+]i.

scholarly journals Pseudorabies Virus US3 Protein Kinase Protects Infected Cells from NK Cell-Mediated Lysis via Increased Binding of the Inhibitory NK Cell Receptor CD300a

2015 ◽  
Vol 90 (3) ◽  
pp. 1522-1533 ◽  
Author(s):  
K. Grauwet ◽  
M. Vitale ◽  
S. De Pelsmaeker ◽  
T. Jacob ◽  
K. Laval ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Nk Cells ◽  
Natural Killer ◽  
Pseudorabies Virus ◽  
Nk Cell ◽  
Cell Receptor ◽  
Target Cells ◽  
Group I ◽  
Infected Cells ◽  
Nk Cell Receptor

ABSTRACTSeveral reports have indicated that natural killer (NK) cells are of particular importance in the innate response against herpesvirus infections. As a consequence, herpesviruses have developed diverse mechanisms for evading NK cells, although few such mechanisms have been identified for the largest herpesvirus subfamily, the alphaherpesviruses. The antiviral activity of NK cells is regulated by a complex array of interactions between activating/inhibitory receptors on the NK cell surface and the corresponding ligands on the surfaces of virus-infected cells. Here we report that the US3 protein kinase of the alphaherpesvirus pseudorabies virus (PRV) displays previously uncharacterized immune evasion properties: it triggers the binding of the inhibitory NK cell receptor CD300a to the surface of the infected cell, thereby providing increased CD300a-mediated protection of infected cells against NK cell-mediated lysis. US3-mediated CD300a binding was found to depend on aminophospholipid ligands of CD300a and on group I p21-activated kinases. These data identify a novel alphaherpesvirus strategy for evading NK cells and demonstrate, for the first time, a role for CD300a in regulating NK cell activity upon contact with virus-infected target cells.IMPORTANCEHerpesviruses have developed fascinating mechanisms to evade elimination by key elements of the host immune system, contributing to their ability to cause lifelong infections with recurrent reactivation events. Natural killer (NK) cells are central in the innate antiviral response. Here we report that the US3 protein kinase of the alphaherpesvirus pseudorabies virus displays a previously uncharacterized capacity for evasion of NK cells. Expression of US3 protects infected cells from NK cell-mediated lysis via increased binding of the inhibitory NK cell receptor CD300a. We show that this US3-mediated increase in CD300a binding depends on aminophospholipids and on cellular p21-activated kinases (PAKs). The identification of this novel NK cell evasion strategy may contribute to the design of improved herpesvirus vaccines and may also have significance for other PAK- and CD300a-modulating viruses and cancer cells.

scholarly journals Association with FcRγ Is Essential for Activation Signal through NKR-P1 (CD161) in Natural Killer (NK) Cells and NK1.1+ T Cells

1997 ◽  
Vol 186 (12) ◽  
pp. 1957-1963 ◽  
Author(s):  
Noriko Arase ◽  
Hisashi Arase ◽  
Seung Yong Park ◽  
Hiroshi Ohno ◽  
Chisei Ra ◽  
...  
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Activation ◽  
Nk Cell ◽  
Cross Linking ◽  
Primary Host ◽  
Receptor Complexes ◽  
Ifn Γ ◽  
Deficient Mice

Natural killer (NK) cells exhibit cytotoxicity against variety of tumor cells and virus-infected cells without prior sensitization and represent unique lymphocytes involved in primary host defense. NKR-P1 is thought to be one of NK receptors mediating activation signals because cross-linking of NKR-P1 activates NK cells to exhibit cytotoxicity and IFN-γ production. However, molecular mechanism of NK cell activation via NKR-P1 is not well elucidated. In this study, we analyzed the cell surface complex associated with NKR-P1 on NK cells and found that NKR-P1 associates with the FcRγ chain which is an essential component of Fc receptors for IgG and IgE. The association between FcRγ and NKR-P1 is independent of Fc receptor complexes. Furthermore, NK cells from FcRγ-deficient mice did not show cytotoxicity or IFN-γ production upon NKR-P1 cross-linking. Similarly, NK1.1+ T cells from FcRγ-deficient mice did not produce IFN-γ upon NKR-P1 crosslinking. These findings demonstrate that the FcRγ chain plays an important role in activation of NK cells via the NKR-P1 molecule.

Phase I-II Trial of Adoptive Immunotherapy with Haploidentical KIR Ligand-Mismatched Natural Killer Cells in High Risk Acute Myeloblastic Leukemia Patients.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2857-2857
Author(s):  
Antonio Curti ◽  
Loredana Ruggeri ◽  
Alessandra D’Addio ◽  
Elena Urbani ◽  
Andrea Bontadini ◽  
...  
Keyword(s):  
T Cells ◽  
High Risk ◽  
Complete Remission ◽  
Phase I ◽  
Nk Cells ◽  
Natural Killer ◽  
Adoptive Immunotherapy ◽  
Partial Remission ◽  
Nk Cell ◽  
Target Cells

Abstract Natural killer (NK) cells play a critical role in innate immunity and are relevant for the immune control of tumors. Their effector function is regulated by a number of activating and inhibitory receptors, termed killer immunoglobulin receptors (KIRs). In haploidentical T-cell depleted transplantation the donor/recipient KIR mismatch significantly impacts on tumor cell killing, particularly in acute myeloid leukemia (AML). Therefore, haploidentical KIR-mismatched NK cells may be used as adoptive immunotherapy for high risk AML patients in non-transplantation settings. Thirty-one high risk AML patients entered a phase I-II study of NK-cell based immunotherapy and were screened for the avalilability of one haploidentical KIR ligand mismatched donor. Ten of them resulted as having one suitable donor. NK cells were enriched from steady-state leukaphereses by using a double-step immunomagnetic separation system (Miltenyi Biotec, Germany), consisting in depletion of CD3+ T cells followed by positive selection of CD56+ NK cells, and then cryopreserved. CD56+ NK cells were enriched from 8.28±3.7% to 85.9±3.2% (recovery 67.9±15%, viability >92%). So far, 8 patients (1 partial remission, 4 progressions and 3 complete remissions) received NK cell infusion which was preceeded by immunosuppressive chemotherapy, including fludarabine 125 mg/m2 and cyclophosphamide 4g/m2. AML patients received 6 subcutaneous injections of interleukin 2 (IL-2) after adoptive immunotherapy. The median number of reinfused NK cells was 3.6 × 106/Kg and contaminating CD3+ T cells were always less than 1×105/Kg. NK cells were capable to kill NK-sensitive K562 cells in a flow-cytometry-based cytotoxicity assay. The procedure was well-tolerated and no significant toxicity, including GVHD, related to NK cell infusion was observed. The patient in partial remission obtained a complete remission, which lasted for 6 months; among the 4 patients with active/progressive disease 2 patients showed the persistence of disease and one patient died during the aplastic phase. The 3 patients in complete remission are stable after 5, 3 and 4 months of follow up. By using a RT-PCR-based chimerism assay, we demonstrated the presence of adoptively transferred NK cells in 2/4 patients with a peak in circulating NK cell number at day 12 after infusion. Functional biological studies demonstrated the presence of alloreactive NK cell clones in all the donors (at the frequencies of 11 ± 4%) and in 3/4 patients (at the frequences of 16 ± 5%) only at day 3 after infusion of NK cells. In summary, a two-step enrichment of CD56+ NK cells allows the collection of a suitable number of target cells to be used as adoptive immunotherapy in AML patients. Infusion of cryopreserved NK cells is feasible and safe and adoptively transferred NK cells can be detected in the peripheral blood after infusion.

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