scholarly journals Coronaviruses induce the expression of the peptide antigen transporter TAP1.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Host Cell ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
The United States ◽  
Class I ◽  
Class I Mhc ◽  
Mhc I

Coronavirus infection is an emerging public health threat in the United States and worldwide (1). We mined published microarray data to perform systems-level analysis of host cell transcription following infection with multiple coronavirus types in order to identify therapeutic targets and host cell vulnerabilities (2, 3). We identified the antigen peptide transported TAP1 as differentially expressed in vitro in a human cell line following infection with human coronavirus 229E and in vivo in the lungs of mice following infection with the severe acute respiratory distress syndrome SARS coronavirus. While TAP1 functions to enhance presentation of class I-associated peptides to CD8 cytotoxic T-cells, TAP1 also enhances presentation of major histocompatibility class I (MHC-I) receptors (4). One criteria natural killer cells use to lyse cells is the absence of surface MHC-I (5), and hepatitis C virus up-regulates TAP1 to increase surface expression of MHC-I and inhibit NK-cell cytotoxicity and promote infection (6). We propose coronaviruses similarly up-regulate TAP1 to impair natural killer cell-mediated cytotoxicity responses and avoid recognition by NK cells.

scholarly journals Cytomegalovirus immunoevasin reveals the physiological role of “missing self” recognition in natural killer cell dependent virus control in vivo

2010 ◽  
Vol 207 (12) ◽  
pp. 2663-2673 ◽  
Author(s):  
Marina Babić ◽  
Michal Pyzik ◽  
Biljana Zafirova ◽  
Maja Mitrović ◽  
Višnja Butorac ◽  
...  
Keyword(s):  
Natural Killer ◽  
Cell Activation ◽  
Nk Cell ◽  
Killer Cell ◽  
Physiological Role ◽  
Dependent Manner ◽  
Class I Mhc ◽  
Mhc I ◽  
Missing Self

Cytomegaloviruses (CMVs) are renowned for interfering with the immune system of their hosts. To sidestep antigen presentation and destruction by CD8+ T cells, these viruses reduce expression of major histocompatibility complex class I (MHC I) molecules. However, this process sensitizes the virus-infected cells to natural killer (NK) cell–mediated killing via the “missing self” axis. Mouse cytomegalovirus (MCMV) uses m152 and m06 encoded proteins to inhibit surface expression of MHC I molecules. In addition, it encodes another protein, m04, which forms complexes with MHC I and escorts them to the cell surface. This mechanism is believed to prevent NK cell activation and killing by restoring the “self” signature and allowing the engagement of inhibitory Ly49 receptors on NK cells. Here we show that MCMV lacking m04 was attenuated in an NK cell– and MHC I–dependent manner. NK cell–mediated control of the infection was dependent on the presence of NK cell subsets expressing different inhibitory Ly49 receptors. In addition to providing evidence for immunoevasion strategies used by CMVs to avoid NK cell control via the missing-self pathway, our study is the first to demonstrate that missing self–dependent NK cell activation is biologically relevant in the protection against viral infection in vivo.

scholarly journals Functional Dichotomy in Natural Killer Cell Signaling

2001 ◽  
Vol 193 (12) ◽  
pp. 1413-1424 ◽  
Author(s):  
Francesco Colucci ◽  
Eleftheria Rosmaraki ◽  
Søren Bregenholt ◽  
Sandrine I. Samson ◽  
Vincenzo Di Bartolo ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Surface Receptors ◽  
Nk T Cells ◽  
Nk Cell Differentiation ◽  
Ifn Γ

The product of the protooncogene Vav1 participates in multiple signaling pathways and is a critical regulator of antigen–receptor signaling in B and T lymphocytes, but its role during in vivo natural killer (NK) cell differentiation is not known. Here we have studied NK cell development in Vav1−/− mice and found that, in contrast to T and NK-T cells, the absolute numbers of phenotypically mature NK cells were not reduced. Vav1−/− mice produced normal amounts of interferon (IFN)-γ in response to Listeria monocytogenes and controlled early infection but showed reduced tumor clearance in vivo. In vitro stimulation of surface receptors in Vav1−/− NK cells resulted in normal IFN-γ production but reduced tumor cell lysis. Vav1 was found to control activation of extracellular signal-regulated kinases and exocytosis of cytotoxic granules. In contrast, conjugate formation appeared to be only mildly affected, and calcium mobilization was normal in Vav1−/− NK cells. These results highlight fundamental differences between proximal signaling events in T and NK cells and suggest a functional dichotomy for Vav1 in NK cells: a role in cytotoxicity but not for IFN-γ production.

scholarly journals Monocytes control natural killer cell differentiation to effector phenotypes

Blood ◽  
2011 ◽  
Vol 117 (17) ◽  
pp. 4511-4518 ◽  
Author(s):  
Katrina Soderquest ◽  
Nick Powell ◽  
Carmelo Luci ◽  
Nico van Rooijen ◽  
Andrés Hidalgo ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
In Vivo Model ◽  
Dependent Manner ◽  
Nk Cell Differentiation

Abstract Natural killer (NK) cells play a major role in immunologic surveillance of cancer. Whether NK-cell subsets have specific roles during antitumor responses and what the signals are that drive their terminal maturation remain unclear. Using an in vivo model of tumor immunity, we show here that CD11bhiCD27low NK cells migrate to the tumor site to reject major histocompatibility complex class I negative tumors, a response that is severely impaired in Txb21−/− mice. The phenotypical analysis of Txb21-deficient mice shows that, in the absence of Txb21, NK-cell differentiation is arrested specifically at the CD11bhiCD27hi stage, resulting in the complete absence of terminally differentiated CD11bhiCD27low NK cells. Adoptive transfer experiments and radiation bone marrow chimera reveal that a Txb21+/+ environment rescues the CD11bhiCD27hi to CD11bhiCD27low transition of Txb21−/− NK cells. Furthermore, in vivo depletion of myeloid cells and in vitro coculture experiments demonstrate that spleen monocytes mediate the terminal differentiation of peripheral NK cells in a Txb21- and IL-15Rα–dependent manner. Together, these data reveal a novel, unrecognized role for Txb21 expression in monocytes in promoting NK-cell development and help appreciate how various NK-cell subsets are generated and participate in antitumor immunity.

scholarly journals Interactions of Human Myeloid Cells with Natural Killer Cell Subsets In Vitro and In Vivo

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Obinna Chijioke ◽  
Christian Münz
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Experimental Models ◽  
Human Pathogens ◽  
Innate And Adaptive Immunity ◽  
Antigen Presenting

In both human and mouse it has been recently realized that natural killer (NK) cells do not emerge from the bone marrow with full functional competence but rather acquire functions in interaction with antigen-presenting cells (APCs), primarily dendritic cells (DCs). Here we review the mechanisms and the consequences of this NK-cell preactivation, as well as discuss new experimental models that now allow investigating these interactions for human NK cells and their response to human pathogens in vivo. These investigations will allow harnessing NK cells during vaccination for improved innate and adaptive immunity.

scholarly journals Prevention of embryo loss in non-obese diabetic mice using adoptive ITGA2+ISG20+ natural killer-cell transfer

Reproduction ◽  
2009 ◽  
Vol 137 (6) ◽  
pp. 943-955 ◽  
Author(s):  
Yi Lin ◽  
Huiqi Wang ◽  
Wenjing Wang ◽  
Shan Zeng ◽  
Yanmin Zhong ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Nod Mice ◽  
Cxcl12 Expression ◽  
Pregnant Mice ◽  
Embryo Loss

Both regulatory T cells and regulatory natural killer (NK) cells may play essential roles in the maintenance of pregnancy. In this study, we show that a significantly high percentage of spontaneous embryo loss was observed in both allogeneic and syngeneic pregnant non-obese diabetic (NOD) mice. The percentage of embryo loss in allogeneic pregnant mice was further increased by the administration of anti-asialo ganglio-N-tetraosylceramide to deplete NK cells, but was decreased by the adoptive transfer of ITGA2+ISG20+ (CD49b+ CD25+) NK cells from normal mice. No such trend was observed in syngeneic pregnant NOD mice. The pattern of CXCR4 (specific receptor for CXCL12) expression on NK cells was analyzed and NK-cell migration was confirmed by in vitro and in vivo migratory assays. Since CXCL12 production by murine trophoblast cells was confirmed previously, our findings suggest that the recruitment of peripheral CXCR4-expressing ITGA2+ISG20+ NK cells into pregnant uteri may be important in the regulation of feto-maternal tolerance.

scholarly journals Immunoreceptor tyrosine-based inhibitory motif–dependent functions of an MHC class I-specific NK cell receptor

2017 ◽  
Vol 114 (40) ◽  
pp. E8440-E8447 ◽  
Author(s):  
Michael D. Bern ◽  
Diana L. Beckman ◽  
Takashi Ebihara ◽  
Samantha M. Taffner ◽  
Jennifer Poursine-Laurent ◽  
...  
Keyword(s):  
Nk Cells ◽  
Mhc Class I ◽  
Nk Cell ◽  
Single Gene ◽  
Cell Receptor ◽  
Class I ◽  
Class I Mhc ◽  
Mhc I ◽  
Receptor Repertoire

Natural killer (NK) cells express MHC class I (MHC-I)-specific receptors, such as Ly49A, that inhibit killing of cells expressing self–MHC-I. Self–MHC-I also “licenses” NK cells to become responsive to activating stimuli and regulates the surface level of NK-cell inhibitory receptors. However, the mechanisms of action resulting from these interactions of the Ly49s with their MHC-I ligands, particularly in vivo, have been controversial. Definitive studies could be derived from mice with targeted mutations in inhibitory Ly49s, but there are inherent challenges in specifically altering a single gene within a multigene family. Herein, we generated a knock-in mouse with a targeted mutation in the immunoreceptor tyrosine-based inhibitory motif (ITIM) of Ly49A that abolished the inhibitory function of Ly49A in cytotoxicity assays. This mutant Ly49A caused a licensing defect in NK cells, but the surface expression of Ly49A was unaltered. Moreover, NK cells that expressed this mutant Ly49A exhibited an altered inhibitory receptor repertoire. These results demonstrate that Ly49A ITIM signaling is critical for NK-cell effector inhibition, licensing, and receptor repertoire development.

scholarly journals Critical role for the Ly49 family of class I MHC receptors in adaptive natural killer cell responses

2018 ◽  
Vol 115 (45) ◽  
pp. 11579-11584 ◽  
Author(s):  
Andrew Wight ◽  
Ahmad Bakur Mahmoud ◽  
Michal Scur ◽  
Megan M. Tu ◽  
Mir Munir A. Rahim ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Critical Role ◽  
Killer Cell ◽  
Class I ◽  
Antigen Specificity ◽  
Cell Memory ◽  
Class I Mhc ◽  
Memory Response

Adaptive natural killer (NK) cell memory represents a new frontier in immunology. Work over the last decade has discovered and confirmed the existence of NK cells with antigen-specific memories, which had previously been considered a unique property of T and B cells. These findings have shown that antigen-specific NK cells gain their specificity without the use of RAG proteins, representing a novel mechanism for generating antigen specificity, but the details of this mechanism have remained a mystery. We have discovered that members of the Ly49 family of surface receptors are critically involved in both the sensitization and the challenge phases of an NK cell memory response, as is antigen presentation from their binding partner, the class I MHC. Moreover, we demonstrate that the Ly49-interacting component of a presented antigen dictates the specificity of the NK cell memory response, implicating Ly49 receptors themselves in antigen-specific recognition. Finally, we demonstrate that adaptive NK cell memories can protect against an otherwise lethal melanoma without T cell or B cell support. These findings offer insight into the mechanism behind NK cell antigen specificity and demonstrate the clinical potential of this adaptive immune cell.

scholarly journals Neutrophil depletion impairs natural killer cell maturation, function, and homeostasis

2012 ◽  
Vol 209 (3) ◽  
pp. 565-580 ◽  
Author(s):  
Baptiste N. Jaeger ◽  
Jean Donadieu ◽  
Céline Cognet ◽  
Claire Bernat ◽  
Diana Ordoñez-Rueda ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Immature Stage ◽  
Immune Defense ◽  
Cell Reactivity ◽  
Cell Functions

Natural killer (NK) cells are bone marrow (BM)–derived granular lymphocytes involved in immune defense against microbial infections and tumors. In an N-ethyl N-nitrosourea (ENU) mutagenesis strategy, we identified a mouse mutant with impaired NK cell reactivity both in vitro and in vivo. Dissection of this phenotype showed that mature neutrophils were required both in the BM and in the periphery for proper NK cell development. In mice lacking neutrophils, NK cells displayed hyperproliferation and poor survival and were blocked at an immature stage associated with hyporesponsiveness. The role of neutrophils as key regulators of NK cell functions was confirmed in patients with severe congenital neutropenia and autoimmune neutropenia. In addition to their direct antimicrobial activity, mature neutrophils are thus endowed with immunoregulatory functions that are conserved across species. These findings reveal novel types of cooperation between cells of the innate immune system and prompt examination of NK cell functional deficiency in patients suffering from neutropenia-associated diseases.

scholarly journals The chemoattractant chemerin suppresses melanoma by recruiting natural killer cell antitumor defenses

2012 ◽  
Vol 209 (8) ◽  
pp. 1427-1435 ◽  
Author(s):  
Russell K. Pachynski ◽  
Brian A. Zabel ◽  
Holbrook E. Kohrt ◽  
Nicole M. Tejeda ◽  
Justin Monnier ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Natural Killer ◽  
Messenger Rna ◽  
Nk Cell ◽  
Killer Cell ◽  
Relative Reduction ◽  
Melanoma Tumor ◽  
In Vitro Proliferation

Infiltration of specialized immune cells regulates the growth and survival of neoplasia. Here, in a survey of public whole genome expression datasets we found that the gene for chemerin, a widely expressed endogenous chemoattractant protein, is down-regulated in melanoma as well as other human tumors. Moreover, high chemerin messenger RNA expression in tumors correlated with improved outcome in human melanoma. In experiments using the B16 transplantable mouse melanoma, tumor-expressed chemerin inhibited in vivo tumor growth without altering in vitro proliferation. Growth inhibition was associated with an altered profile of tumor-infiltrating cells with an increase in natural killer (NK) cells and a relative reduction in myeloid-derived suppressor cells and putative immune inhibitory plasmacytoid dendritic cells. Tumor inhibition required host expression of CMKLR1 (chemokine-like receptor 1), the chemoattractant receptor for chemerin, and was abrogated by NK cell depletion. Intratumoral injection of chemerin also inhibited tumor growth, suggesting the potential for therapeutic application. These results show that chemerin, whether expressed by tumor cells or within the tumor environment, can recruit host immune defenses that inhibit tumorigenesis and suggest that down-regulation of chemerin may be an important mechanism of tumor immune evasion.

scholarly journals Adenovirus vector delivery stimulates natural killer cell recognition

2007 ◽  
Vol 88 (4) ◽  
pp. 1103-1108 ◽  
Author(s):  
Peter Tomasec ◽  
Eddie C. Y. Wang ◽  
Veronika Groh ◽  
Thomas Spies ◽  
Brian P. McSharry ◽  
...  
Keyword(s):  
Natural Killer ◽  
Inflammatory Responses ◽  
Nk Cell ◽  
Cell Clone ◽  
Human Fibroblasts ◽  
Killer Cell ◽  
Adenovirus Vector ◽  
Vector Delivery

We report that delivery of first-generation replication-deficient adenovirus (RDAd) vectors into primary human fibroblasts is associated with the induction of natural killer (NK) cell-mediated cytolysis in vitro. RDAd vector delivery induced cytolysis by a range of NK cell populations including the NK cell clone NKL, primary polyclonal NK lines and a proportion of NK clones (36 %) in autologous HLA-matched assays. Adenovirus-induced cytolysis was inhibited by antibody blocking of the NK-activating receptor NKG2D, implicating this receptor in this function. NKG2D is ubiquitously expressed on NK cells and CD8+ T cells. Significantly, γ-irradiation of the vector eliminated the effect, suggesting that breakthrough expression from the vector induces at least some of the pro-inflammatory responses of unknown aetiology following the application of RDAd vectors during in vivo gene delivery.

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