Faculty Opinions recommendation of Type I IFN promotes NK cell expansion during viral infection by protecting NK cells against fratricide.

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.

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

Journal of Experimental Medicine ◽

10.1084/jem.20150712 ◽

2016 ◽

Vol 213 (2) ◽

pp. 225-233 ◽

Cited By ~ 78

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.

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Activating receptors promote NK cell expansion for maintenance, IL-10 production, and CD8 T cell regulation during viral infection

Journal of Experimental Medicine ◽

10.1084/jem.20082387 ◽

2009 ◽

Vol 206 (10) ◽

pp. 2235-2251 ◽

Cited By ~ 134

Author(s):

Seung-Hwan Lee ◽

Kwang-Sin Kim ◽

Nassima Fodil-Cornu ◽

Silvia M. Vidal ◽

Christine A. Biron

Keyword(s):

T Cell ◽

Immune Responses ◽

Viral Infection ◽

Nk Cells ◽

Cell Expansion ◽

Nk Cell ◽

Cd8 T Cell ◽

Adaptive Immune Responses ◽

Adaptive Immune ◽

Activating Receptors

Natural killer (NK) cells have the potential to deliver both direct antimicrobial effects and regulate adaptive immune responses, but NK cell yields have been reported to vary greatly during different viral infections. Activating receptors, including the Ly49H molecule recognizing mouse cytomegalovirus (MCMV), can stimulate NK cell expansion. To define Ly49H's role in supporting NK cell proliferation and maintenance under conditions of uncontrolled viral infection, experiments were performed in Ly49h−/−, perforin 1 (Prf1)−/−, and wild-type (wt) B6 mice. NK cell numbers were similar in uninfected mice, but relative to responses in MCMV-infected wt mice, NK cell yields declined in the absence of Ly49h and increased in the absence of Prf1, with high rates of proliferation and Ly49H expression on nearly all cells. The expansion was abolished in mice deficient for both Ly49h and Prf1 (Ly49h−/−Prf1−/−), and negative consequences for survival were revealed. The Ly49H-dependent protection mechanism delivered in the absence of Prf1 was a result of interleukin 10 production, by the sustained NK cells, to regulate the magnitude of CD8 T cell responses. Thus, the studies demonstrate a previously unappreciated critical role for activating receptors in keeping NK cells present during viral infection to regulate adaptive immune responses.

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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

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0552 ◽

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.

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

Journal of Experimental Medicine ◽

10.1084/jem.184.5.2043 ◽

1996 ◽

Vol 184 (5) ◽

pp. 2043-2048 ◽

Cited By ~ 97

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.

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

10.1101/2021.05.11.443590 ◽

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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MYC Oncogene Abrogates Natural Killer (NK) Cell-Mediated Immune Surveillance of B- and T- Lymphoid Malignancies By Suppressing STAT1/2-Type I IFN Signaling

Blood ◽

10.1182/blood-2019-122607 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 730-730

Author(s):

Srividya Swaminathan ◽

Line Dam Heftdal ◽

Daniel Liefwalker ◽

Renumathy Dhanasekaran ◽

Anja Deutzmann ◽

...

Keyword(s):

Nk Cells ◽

Natural Killer ◽

Nk Cell ◽

Immune Surveillance ◽

Cell Maturation ◽

Type I ◽

Type I Ifn ◽

Myc Oncogene ◽

Lymphoid Malignancies ◽

Type I Ifns

Background: Many high-risk B- and T- lymphoid malignancies including Acute Lymphoblastic Leukemia (ALL) and lymphomas exhibit hyperactivation of the MYC oncogene and MYC-associated pathways. Experimentally, direct targeting of MYC in mouse models of MYCHigh lymphoid cancers sustains tumor regression. However, the requirement of MYC in normal lymphocyte physiology has impeded the development of MYC inhibitors. Hence, the development of targeted therapies against MYCHigh lymphoid cancers requires the identification of cell-intrinsic and cell-extrinsic (immune microenvironment) processes uniquely regulated by 'oncogenic' MYC (MYCHigh B/T-lymphoblasts) but not by 'normal' MYC (MYCLow B/T-lymphocytes). Approach: We employed an inducible transgenic mouse model of MYC-driven T-ALL (SRα-tTA/Tet-O-hMYC mice; Felsher and Bishop, Molecular Cell, 1999) to study leukemia-intrinsic, and leukemia-extrinsic immune surveillance mechanisms upon MYC activation (MYCHigh/ON, overt T-ALL), and MYC inactivation (MYCLow/OFF, regressed T-ALL). Inducible regulation of the human MYC (hMYC) transgene specifically in T-lymphoblasts enables us to elucidate how T-ALL-intrinsic MYC impacts normal immune cells during leukemogenesis in vivo. Using mass cytometry (CyTOF), and CIBERSORT to profile the immune microenvironment of MYCHigh/ON and MYCLow/OFF T-ALLs in SRα-tTA/Tet-O-hMYC mice, we identified specific anti- and pro-tumorigenic immune subsets that can be modulated to develop targeted immunotherapies against MYC-driven lymphoid cancers. Results: By conducting CyTOF-based immune profiling of lymphoid organs in healthy mice, and mice bearing MYCON or MYCOFF T-ALL, we demonstrated a significant reduction in numbers of Natural Killer (NK) cells, and an increase in the absolute counts of neutrophils and dendritic cells (DCs) in MYCON mice, in comparison to healthy controls and MYCOFF mice. The reduction in NK cell numbers in MYCON mice led us to hypothesize that the NK subset may play an anti-tumorigenic role in MYC-driven T-ALLs. Since anti-tumor immune subsets can be developed as therapies against MYC-driven lymphoid cancers, we decided to focus on how MYC impacts NK cell-mediated immune surveillance. We demonstrated that mature CD3-NKp46+ Natural Killer (NK) cells are specifically 'excluded' from the T-ALL microenvironment, in a MYC-dependent fashion. Residual NK cells in MYCON T-ALL-bearing mice exhibited suppression of the NK cell maturation/cytotoxicity marker, NKp46. Concordant with the suppression of NKp46 on NK cells in MYCON mice, we observed a blockade in early NK cell development from the NK precursor (NKP) to the immature NK (iNK) stage which is marked by the expression of NKp46. Next, we showed that adoptive transfer of mature CD3- NKp46+ syngeneic NK cells alone is sufficient to delay the initiation of MYCON T-ALL, and the recurrence of MYCOFF T-ALL. Further investigation into the molecular mechanism behind blockade of NK cell maturation in MYC-driven B/T-lymphoid cancers revealed that cancer-intrinsic MYC transcriptionally represses STAT1/2-Type I IFN signaling required for early NK cell maturation from NKP to iNK stage. We observed that treating T-ALL-bearing SRα-tTA/Tet-O-hMYC mice (MYCON)with Type I IFN improves survival by rescuing NK cell maturation. We showed that that low expression of both STAT1 and STAT2 in patients with MYCHigh B- and T-lymphoid neoplasms correlates significantly with the absence of activated NK cells, and predicts unfavorable clinical outcomes. Of note, aggressive MYCHigh B/T-lymphoid cancers are often treated with Type I IFNs, but the molecular mechanisms underlying the anti-cancer properties of Type I IFNs are not completely understood. We demonstrate for the first time that MYC-mediated suppression of NK surveillance may in part be responsible for the sensitivity of B/T-lymphoid cancers to Type I IFN therapy. Conclusion: We conclude that subversion of NK cell-mediated immune surveillance is critical for MYC-induced leukemogenesis. Our studies thus provide a rationale for developing targeted NK cell-based therapies as alternatives to direct MYC inhibition for treating refractory MYCHigh B- and T- lymphoid malignancies. Disclosures No relevant conflicts of interest to declare.

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