scholarly journals Type I IFN promotes NK cell expansion during viral infection by protecting NK cells against fratricide

2016 ◽  
Vol 213 (2) ◽  
pp. 225-233 ◽  
Author(s):  
Sharline Madera ◽  
Moritz Rapp ◽  
Matthew A. Firth ◽  
Joshua N. Beilke ◽  
Lewis L. Lanier ◽  
...  
Keyword(s):  
Viral Infection ◽  
Nk Cells ◽  
Nk Cell ◽  
Cell Formation ◽  
Memory Cell ◽  
Type I ◽  
Dependent Manner ◽  
Type I Ifn ◽  
Mcmv Infection ◽  
Adaptive Immune Cells

Type I interferon (IFN) is crucial in host antiviral defense. Previous studies have described the pleiotropic role of type I IFNs on innate and adaptive immune cells during viral infection. Here, we demonstrate that natural killer (NK) cells from mice lacking the type I IFN-α receptor (Ifnar−/−) or STAT1 (which signals downstream of IFNAR) are defective in expansion and memory cell formation after mouse cytomegalovirus (MCMV) infection. Despite comparable proliferation, Ifnar−/− NK cells showed diminished protection against MCMV infection and exhibited more apoptosis compared with wild-type NK cells. Furthermore, we show that Ifnar−/− NK cells express increased levels of NK group 2 member D (NKG2D) ligands during viral infection and are susceptible to NK cell–mediated fratricide in a perforin- and NKG2D-dependent manner. Adoptive transfer of Ifnar−/− NK cells into NK cell–deficient mice reverses the defect in survival and expansion. Our study reveals a novel type I IFN–dependent mechanism by which NK cells evade mechanisms of cell death after viral infection.

scholarly journals Inflammatory monocytes require type I interferon receptor signaling to activate NK cells via IL-18 during a mucosal viral infection

2017 ◽  
Vol 214 (4) ◽  
pp. 1153-1167 ◽  
Author(s):  
Amanda J. Lee ◽  
Branson Chen ◽  
Marianne V. Chew ◽  
Nicole G. Barra ◽  
Mira M. Shenouda ◽  
...  
Keyword(s):  
Viral Infection ◽  
Nk Cells ◽  
Cell Activation ◽  
Cell Function ◽  
Nk Cell ◽  
Type I Interferon ◽  
Underlying Mechanism ◽  
Type I ◽  
Type I Ifn ◽  
Inflammatory Monocytes

The requirement of type I interferon (IFN) for natural killer (NK) cell activation in response to viral infection is known, but the underlying mechanism remains unclear. Here, we demonstrate that type I IFN signaling in inflammatory monocytes, but not in dendritic cells (DCs) or NK cells, is essential for NK cell function in response to a mucosal herpes simplex virus type 2 (HSV-2) infection. Mice deficient in type I IFN signaling,Ifnar−/−andIrf9−/−mice, had significantly lower levels of inflammatory monocytes, were deficient in IL-18 production, and lacked NK cell–derived IFN-γ. Depletion of inflammatory monocytes, but not DCs or other myeloid cells, resulted in lower levels of IL-18 and a complete abrogation of NK cell function in HSV-2 infection. Moreover, this resulted in higher susceptibility to HSV-2 infection. AlthoughIl18−/−mice had normal levels of inflammatory monocytes, their NK cells were unresponsive to HSV-2 challenge. This study highlights the importance of type I IFN signaling in inflammatory monocytes and the induction of the early innate antiviral response.

scholarly journals Pro-apoptotic caspase deficiency reveals a cell-extrinsic mechanism of NK cell regulation

2021 ◽  
Author(s):  
Tayla M. Olsen ◽  
Wei Hong Tan ◽  
Arne C. Knudsen ◽  
Anthony Rongvaux
Keyword(s):  
Cell Death ◽  
Nk Cells ◽  
Nk Cell ◽  
Apoptotic Cell ◽  
Type I ◽  
Dependent Manner ◽  
Apoptosis Pathway ◽  
A Cell

AbstractRegulated cell death is essential for the maintenance of cellular and tissue homeostasis. In the hematopoietic system, genetic defects in apoptotic cell death generally produce the accumulation of immune cells, inflammation and autoimmunity. In contrast, we found that genetic deletion of caspases of the mitochondrial apoptosis pathway reduces natural killer (NK) cell numbers and makes NK cells functionally defective in vivo and in vitro. Caspase deficiency results in constitutive activation of a type I interferon (IFN) response, due to leakage of mitochondrial DNA and activation of the cGAS/STING pathway. The NK cell defect in caspase-deficient mice is independent of the type I IFN response, but the phenotype is partially rescued by cGAS or STING deficiency. Finally, caspase deficiency alters NK cells in a cell-extrinsic manner. Type I IFNs and NK cells are two essential effectors of antiviral immunity, and our results demonstrate that they are both regulated in a caspase-dependent manner. Beyond caspase-deficient animals, our observations may have implications in infections that trigger mitochondrial stress and caspase-dependent cell death.

552 SUMOylation inhibitor TAK-981 activates NK cells and macrophages via Type I interferon signaling and shows synergistic activity in combination with rituximab and daratumumab in preclinical models

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A588-A588
Author(s):  
Akito Nakamura ◽  
Keli Song ◽  
Stephen Grossman ◽  
Kristina Xega ◽  
Yuhong Zhang ◽  
...  
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Phase 1 ◽  
Neutralizing Antibody ◽  
Type I ◽  
Synergistic Activity ◽  
Type I Ifn ◽  
Innate Immune Responses ◽  
Preclinical Models ◽  
Xenograft Models

BackgroundTAK-981 is a first-in-class small molecule inhibitor of the SUMO activating enzyme in Phase 1 clinical trials. SUMOylation has previously been implicated in the regulation of innate immune responses and expression of Type I interferons,1 and ex vivo treatment of human and mouse immune cells with TAK-981 results in transcriptional upregulation of IFN-beta and Type I IFN receptor (IFNAR) signaling. We previously showed that TAK-981 increases NK cell activation and M1 macrophage polarization, leading to enhanced ADCC and ADCP in the presence of rituximab.2In vivo, TAK-981 induces IFNAR-dependent antitumor activity and synergizes with rituximab in xenograft-bearing mice.2 3 Here we investigated the mechanism of synergistic activity with rituximab and evaluated the combination of TAK-981 with daratumumab, another therapeutic mAb.MethodsThe role of effector function of rituximab in the mechanism of synergy with TAK-981 was evaluated in OCI-Ly10-bearing SCID mice treated with TAK-981 and the LALA-PG version of rituximab, in which mutations in the Fc region prevent FcγR binding. The combination of TAK-981 and rituximab was also evaluated in OCI-Ly10 tumor-bearing mice in which macrophages and/or NK cells were depleted with clodronate and anti-asialo GM1. TAK-981 in combination with daratumumab was evaluated in two CD38+ xenograft models, Daudi (Burkitt’s lymphoma) and LP-1 (multiple myeloma). To test ADCP activity, Daudi-KILR cells were incubated with human monocyte-derived macrophages (hMDM) treated with TAK-981 in the presence or absence of rituximab or daratumumab, with or without a neutralizing antibody to IFNAR2.ResultsUnlike rituximab, LALA-PG mutated rituximab did not synergize with TAK-981 in OCI-Ly10 tumor-bearing mice, indicating a requirement for Fc effector function. Depletion of macrophages with clodronate or NK cells with anti-asialo GM1 lessened the anti-tumor effect of the TAK-981 and rituximab combination, while dual depletion of macrophages and NK cells had a greater impact. TAK-981 showed synergistic activity in combination with daratumumab in two CD38+ xenograft models, Daudi and LP-1. In vitro, TAK-981-treated hMDM showed increased phagocytic activity against Daudi cells, and this effect was further enhanced in the presence of rituximab or daratumumab but prevented by a neutralizing antibody to IFNAR2.ConclusionsIn preclinical models, TAK-981 synergizes with rituximab through a mechanism involving Type I-IFN dependent enhancement of ADCC and ADCP, and the combination of TAK-981 with daratumumab is also synergistic.ReferencesDecque A, Joffre O, Magalhaes JG, Cossec J-C, Blecher-Gonen R, Lapaquette P, Silvin A, Manel N, Joubert P-E, Seeler J-S, Albert ML, Amit I, Amigorena S, Dejean A. Sumoylation coordinates the repression of inflammatory and anti-viral gene-expression programs during innate sensing. Nat Immunol 2016;17:140–149.Nakamura A, Grossman S, Song K, Idamakanti N, Shaprio G, Huszar D. Inhibition of SUMOylation by TAK-981 induces antitumor innate immune responses by modulating macrophage and NK cell function through Type I IFN pathway activation [abstract]. In: Proceedings of the American Association forCancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Cancer Res 2019;79(13 Suppl):Abstract nr 1523.Huszar D. TAK-981: A first-in-class SUMOylation inhibitor in phase 1 clinical trials promotes a Type I interferon response and antitumor immunity in preclinical models. AACR Annual Meeting 2019, American Association for Cancer Research; Mar 29-Apr 03; Atlanta, GA, US. Session DDT01.

scholarly journals Cell-intrinsic adrenergic signaling controls the adaptive NK cell response to viral infection

2020 ◽  
Vol 217 (4) ◽  
Author(s):  
Carlos Diaz-Salazar ◽  
Regina Bou-Puerto ◽  
Adriana M. Mujal ◽  
Colleen M. Lau ◽  
Madlaina von Hoesslin ◽  
...  
Keyword(s):  
Nervous System ◽  
Viral Infection ◽  
Nk Cells ◽  
Nk Cell ◽  
Clonal Expansion ◽  
Mcmv Infection ◽  
Adrenergic Signaling ◽  
Adrenergic Nervous System ◽  
Lymphocyte Responses ◽  
Innate Lymphocytes

Natural killer (NK) cells are innate lymphocytes that exhibit adaptive features, such as clonal expansion and memory, during viral infection. Although activating receptor engagement and proinflammatory cytokines are required to drive NK cell clonal expansion, additional stimulatory signals controlling their proliferation remain to be discovered. Here, we describe one such signal that is provided by the adrenergic nervous system, and demonstrate that cell-intrinsic adrenergic signaling is required for optimal adaptive NK cell responses. Early during mouse cytomegalovirus (MCMV) infection, NK cells up-regulated Adrb2 (which encodes the β2-adrenergic receptor), a process dependent on IL-12 and STAT4 signaling. NK cell–specific deletion of Adrb2 resulted in impaired NK cell expansion and memory during MCMV challenge, in part due to a diminished proliferative capacity. As a result, NK cell-intrinsic adrenergic signaling was required for protection against MCMV. Taken together, we propose a novel role for the adrenergic nervous system in regulating circulating lymphocyte responses to viral infection.

scholarly journals Interferon-Dependent Induction of Clr-b during Mouse Cytomegalovirus Infection Protects Bystander Cells from Natural Killer Cells via NKR-P1B-Mediated Inhibition

2017 ◽  
Vol 9 (4) ◽  
pp. 343-358 ◽  
Author(s):  
Christina L. Kirkham ◽  
Oscar A. Aguilar ◽  
Tao Yu ◽  
Miho Tanaka ◽  
Aruz Mesci ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Promoter Activity ◽  
Dynamic Range ◽  
Transcriptional Start Site ◽  
Type I ◽  
Type I Ifn ◽  
Mouse Cytomegalovirus ◽  
Mcmv Infection ◽  
Bystander Cells

Natural killer (NK) cells are innate lymphocytes that aid in self-nonself discrimination by recognizing cells undergoing pathological alterations. The NKR-P1B inhibitory receptor recognizes Clr-b, a self-encoded marker of cell health downregulated during viral infection. Here, we show that Clr-b loss during mouse cytomegalovirus (MCMV) infection is predicated by a loss of Clr-b (Clec2d) promoter activity and nascent transcripts, driven in part by MCMV ie3 (M122) activity. In contrast, uninfected bystander cells near MCMV-infected fibroblasts reciprocally upregulate Clr-b expression due to paracrine type-I interferon (IFN) signaling. Exposure of fibroblasts to type-I IFN augments Clec2d promoter activity and nascent Clr-b transcripts, dependent upon a cluster of IRF3/7/9 motifs located ∼200 bp upstream of the transcriptional start site. Cells deficient in type-I IFN signaling components revealed IRF9 and STAT1 as key transcription factors involved in Clr-b upregulation. In chromatin immunoprecipitation experiments, the Clec2d IRF cluster recruited STAT2 upon IFN-α exposure, confirming the involvement of ISGF3 (IRF9/STAT1/STAT2) in positively regulating the Clec2d promoter. These findings demonstrate that Clr-b is an IFN-stimulated gene on healthy bystander cells, in addition to a missing-self marker on MCMV-infected cells, and thereby enhances the dynamic range of innate self-nonself discrimination by NK cells.

scholarly journals Oncolytic virus treatment differentially affects the CD56dim and CD56bright NK cell subsets in vivo and regulates a spectrum of human NK cell activity

2020 ◽  
Author(s):  
Michelle Wantoch ◽  
Erica B. Wilson ◽  
Alastair P. Droop ◽  
Sarah L. Phillips ◽  
Matt Coffey ◽  
...  
Keyword(s):  
Nk Cells ◽  
Oncolytic Virus ◽  
Nk Cell ◽  
Direct Action ◽  
Cell Activity ◽  
Type I ◽  
Dependent Manner ◽  
Nk Cell Activity ◽  
Tumour Immunity

AbstractNatural killer (NK) cells protect against intracellular infection and cancer. These properties are exploited in oncolytic virus (OV) therapy, where anti-viral responses enhance anti-tumour immunity. We have analysed the mechanism by which reovirus, an oncolytic dsRNA virus, modulates human NK cell activity. Reovirus activates NK cells in a type I interferon (IFN-I) dependent manner, resulting in STAT1 and STAT4 signalling in both CD56dim and CD56bright NK cell subsets. Gene expression profiling revealed the dominance of IFN-I responses and identified induction of genes associated with NK cell cytotoxicity and cell cycle progression, with distinct responses in the CD56dim and CD56bright subsets. However, reovirus treatment, acting via IFN-I, inhibited NK cell proliferative responses to IL-15 and was associated with reduced AKT signalling. In vivo, human CD56dim and CD56bright NK cells responded with similar kinetics to reovirus treatment, but CD56bright NK cells were transiently lost from the peripheral circulation at the peak of the IFN-I response, suggestive of their redistribution to secondary lymphoid tissue. These results show that reovirus modulates a spectrum of NK cell activity in vivo, encompassing direct action on tumour cells and the regulation of adaptive immunity. Such activity is likely to mirror NK cell responses to natural viral infection.

scholarly journals The transcription factor interferon regulatory factor-1 is essential for natural killer cell function in vivo.

1996 ◽  
Vol 184 (5) ◽  
pp. 2043-2048 ◽  
Author(s):  
G S Duncan ◽  
H W Mittrücker ◽  
D Kägi ◽  
T Matsuyama ◽  
T W Mak
Keyword(s):  
Viral Infection ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Type I ◽  
Regulatory Factor ◽  
Ifn Alpha ◽  
Alpha Beta ◽  
Deficient Mice

The activation of natural killer (NK) cells, cytotoxic lymphocytes capable of major histocompatibility complex (MHC)-unrestricted killing and early antiviral defense, is temporally related to the increased interferon (IFN)-alpha/beta production that is seen in the viral infection of mice. Type I IFN (IFN-alpha/beta) are expressed in many cell types early after primary viral infection and have been shown to mediate resistance against a variety of viruses. In this study, the role of the transcriptional activator IFN regulatory factor-1 (IRF-1) in murine NK cell activity was assessed. IRF-1-deficient mice displayed a normal frequency of NK marker-positive cells, but exhibited greatly reduced NK cell-mediated cytotoxicity after both virus infection and stimulation with the IFN inducer polyinosinic:polycytidilic acid in vivo. In vitro, cytolytic activity in IRF-1-deficient NK cells remained defective after stimulation with IFN-beta, IL-2, and IL-12. IRF-1-deficient mice were unable to eliminate syngeneic MHC class I-negative tumor cells in vivo, and had a reduced ability to reject parental semi-allogeneic donor cells from the circulation. Thus, IRF-1 is essential for the induction of NK cell-mediated cytotoxicity and for the in vivo effector functions that are mediated by this activity.

scholarly journals NK cells mediate clearance of CD8+ T cell–resistant tumors in response to STING agonists

2020 ◽  
Vol 5 (45) ◽  
pp. eaaz2738 ◽  
Author(s):  
Christopher J. Nicolai ◽  
Natalie Wolf ◽  
I-Chang Chang ◽  
Georgia Kirn ◽  
Assaf Marcus ◽  
...  
Keyword(s):  
T Cell ◽  
Nk Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
Tumor Rejection ◽  
Tumor Control ◽  
Type I ◽  
Dependent Manner ◽  
Tumor Models

Several immunotherapy approaches that mobilize CD8+ T cell responses stimulate tumor rejection, and some, such as checkpoint blockade, have been approved for several cancer indications and show impressive increases in patient survival. However, tumors may evade CD8+ T cell recognition via loss of MHC molecules or because they contain few or no neoantigens. Therefore, approaches are needed to combat CD8+ T cell–resistant cancers. STING-activating cyclic dinucleotides (CDNs) are a new class of immune-stimulating agents that elicit impressive CD8+ T cell–mediated tumor rejection in preclinical tumor models and are now being tested in clinical trials. Here, we demonstrate powerful CDN-induced, natural killer (NK) cell–mediated tumor rejection in numerous tumor models, independent of CD8+ T cells. CDNs enhanced NK cell activation, cytotoxicity, and antitumor effects in part by inducing type I interferon (IFN). IFN acted in part directly on NK cells in vivo and in part indirectly via the induction of IL-15 and IL-15 receptors, which were important for CDN-induced NK activation and tumor control. After in vivo administration of CDNs, dendritic cells (DCs) up-regulated IL-15Rα in an IFN-dependent manner. Mice lacking the type I IFN receptor specifically on DCs had reduced NK cell activation and tumor control. Therapeutics that activate NK cells, such as CDNs, checkpoint inhibitors, NK cell engagers, and cytokines, may represent next-generation approaches to cancer immunotherapy.

scholarly journals Natural killer cell immunosuppressive function requires CXCR3-dependent redistribution within lymphoid tissues

2021 ◽  
Author(s):  
Ayad Ali ◽  
Laura M Canaday ◽  
H Alex Feldman ◽  
Hilal Cevik ◽  
MIchael T Moran ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Migration ◽  
T Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Lymphoid Tissues ◽  
Type I ◽  
Type I Ifn ◽  
Cell Suppression

Natural killer (NK) cell suppression of T cells is a key determinant of viral pathogenesis and vaccine efficacy. This process involves perforin-dependent elimination of activated CD4 T cells during the first three days of infection. Although this mechanism requires cell-cell contact, NK cells and T cells typically reside in different compartments of lymphoid tissues at steady state. Here, we show that NK-cell suppression of T cells is associated with a transient accumulation of NK cells within T cell-rich sites of the spleen during lymphocytic choriomeningitis virus infection. The chemokine receptor CXCR3 is required for relocation to T-cell zones and suppression of antiviral T cells. Accordingly, this NK-cell migration is mediated by type I interferon (IFN)-dependent promotion of CXCR3 ligand expression. In contrast, adenoviral vectors that weakly induce type I IFN and do not stimulate NK-cell inhibition of T cells also do not promote measurable redistribution of NK cells to T-cell zones. Provision of supplemental IFN could rescue NK-cell migration during adenoviral vector immunization. Thus, type I IFN and CXCR3 are critical for properly positioning NK cells to constrain antiviral T-cell responses. Development of strategies to curtail migration of NK cells between lymphoid compartments may enhance vaccine-elicited immune responses.

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