Type I IFNs and IL-18 synergistically enhance IFNg production in NK cells by upregulating cMyc-dependent iron metabolism.

2021 ◽  
Author(s):  
Yuliya Skabytska
Keyword(s):  
Nk Cells ◽  
Iron Metabolism ◽  
Type I ◽  
Type I Ifns ◽  
Ifng Production

scholarly journals 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 ◽  
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.

scholarly journals AB0042 CYTOKINE NETWORK ELUCIDATED BY THE QUANTIFICATION OF MULTIPLE CYTOKINES IN THE SERUM SEQUENTIALLY SAMPLED FROM RA PATIENTS WHO WERE TREATED WITH BIOLOGIC DMARDS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1323.2-1324
Author(s):  
K. Sato ◽  
S. Mamada ◽  
C. Hayashi ◽  
T. Nagashima ◽  
S. Minota
Keyword(s):  
Bone Erosion ◽  
Feedback System ◽  
Serum Levels ◽  
Type I Interferons ◽  
Type I ◽  
Serum Samples ◽  
Cytokine Network ◽  
Biologic Dmards ◽  
Type I Ifns ◽  
Before And After

Background:Biologic disease modifying anti-rheumatic drugs (DMARDs) have demonstrated that proinflammatory cytokines such as interleukin (IL-) 6 and tumor necrosis factor (TNF) play important roles in the pathogenesis of rheumatoid arthritis (RA). Other cytokines, such as type I interferons (IFNs), are also implicated in its pathogenesis (ref 1). However, the complete picture of the cytokine network involved in RA remains to be elucidated.Objectives:By quantifying sets of cytokines in the serum of RA patients before and after treatment with various biologic DMARDs, we sought to determine the effects of drugs on (A) type I IFNs, (B) soluble IL-6 receptors, and (C) other cytokines.Methods:52 patients with RA were treated with various biologic DMARDs (tocilizumab (TOC): 16, abatacept (ABT): 15, and TNF inhibitors (TNFi): 21). Serum samples were obtained (1) before, (2) approximately 4 weeks after (3) and approximately 12 weeks after the initiation of treatment. A suspension bead-array system was used for analysis; Bio-Plex Human Cytokine 17-plex Assay kits and Express Custom Panels (Bio-Rad), including IFN-β, IFN-α2, soluble IL-6 receptor α (sIL6Rα) and gp130 were used.Results:(1) As expected, the disease activity score 28-joiny count (DAS28) using the erythrocyte sedimentation rate (ESR) significantly decreased in all three groups (TOC, ABT and TNFi) by 12 weeks.(2) IFN-α2 was barely detected in the serum samples. IFN-β seemed to increase slightly in the ABT group, but the increase was not statistically significant.(3) The levels of sIL6Rα did not change substantially. Those of gp130 decreased slightly but significantly in the TOC group by 12 weeks.(4) The levels of IL-6 decreased significantly in the ABT group by 12 weeks. Those in the TNFi group decreased significantly at 4 weeks but not 12 weeks (Fig. 1A).(5) The levels of IL-7 decreased significantly only in the TOC group (Fig. 1B).Conclusion:(1) The biologic DMARDs tested in this study did not significantly affect the serum levels of type I IFNs in this study.(2) The decrease in gp130 in the TOC group may imply that gp130 is induced by IL-6, although whether this level of decrease has physiological significance is open to question.(3) Serum IL-6 was significantly decreased in the TNFi group at 4 weeks but not 12 weeks. TNF has been reported to induce IL-6 (ref 2), but negative feedback loop(s) may be present. Such a feedback system might make the discontinuation of TNFi difficult, even if patients are in remission.(4) IL-7 may be a target of IL-6. A higher level of IL-7 has been reported to be present in the joints of RA patients compared with osteoarthrosis and it is a cytokine implicated in the differentiation of osteoclasts (ref 3). This may partly explain the effect of TOC on preventing bone erosion in RA.References:[1]Ann Rheum Dis. 2007; 66: 1008–14[2]Rheumatology 2007; 46: 920-6[3]Rheumatology 2008; 47: 753-9Acknowledgments:We thank all the members of the Division of Rheumatology and Clinical Immunology, Department of Medicine, Jichi Medical University. We are also grateful to the patients involved in this study.Disclosure of Interests:Kojiro Sato Grant/research support from: Abbie, Pfizer, Chugai, Astellas, Mitsubishi-Tanabe, Ono, Takeda, Sachiko Mamada: None declared, Chiyomi Hayashi: None declared, Takao Nagashima: None declared, Seiji Minota: None declared

scholarly journals Type I Interferons Regulate the Magnitude and Functionality of Mouse Polyomavirus-Specific CD8 T Cells in a Virus Strain-Dependent Manner

2016 ◽  
Vol 90 (10) ◽  
pp. 5187-5199 ◽  
Author(s):  
Qingsong Qin ◽  
Shwetank ◽  
Elizabeth L. Frost ◽  
Saumya Maru ◽  
Aron E. Lukacher
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Single Amino Acid ◽  
Type I ◽  
Type I Ifns ◽  
Vp1 Capsid Protein

ABSTRACTMouse polyomavirus (MPyV) is a ubiquitous persistent natural mouse pathogen. A glutamic acid (E)-to-glycine (G) difference at position 91 of the VP1 capsid protein shifts the profile of tumors induced by MPyV from an epithelial to a mesenchymal cell origin. Here we asked if this tropism difference affects the MPyV-specific CD8 T cell response, which controls MPyV infection and tumorigenesis. Infection by the laboratory MPyV strain RA (VP1-91G) or a strain A2 mutant with an E-to-G substitution at VP1 residue 91 [A2(91G)] generated a markedly smaller virus-specific CD8 T cell response than that induced by A2(VP1-91E) infection. Mutant A2(91G)-infected mice showed a higher frequency of memory precursor (CD127hiKLRG1lo) CD8 T cells and a higher recall response than those of A2-infected mice. Using T cell receptor (TCR)-transgenic CD8 T cells and immunization with peptide-pulsed dendritic cells, we found that early bystander inflammation associated with A2 infection contributed to recruitment of the larger MPyV-specific CD8 T cell response. Beta interferon (IFN-β) transcripts were induced early during A2 or A2(91G) infections. IFN-β inhibited replication of A2 and A2(91G)in vitro. Using mice lacking IFN-αβ receptors (IFNAR−/−), we showed that type I IFNs played a role in controlling MPyV replicationin vivobut differentially affected the magnitude and functionality of virus-specific CD8 T cells recruited by A2 and A2(91G) viral infections. These data indicate that type I IFNs are involved in protection against MPyV infection and that their effect on the antiviral CD8 T cell response depends on capsid-mediated tropism properties of the MPyV strain.IMPORTANCEIsolates of the human polyomavirus JC virus from patients with the frequently fatal demyelinating brain disease progressive multifocal leukoencephalopathy (PML) carry single amino acid substitutions in the domain of the VP1 capsid protein that binds the sialic acid moiety of glycoprotein/glycolipid receptors on host cells. These VP1 mutations may alter neural cell tropism or enable escape from neutralizing antibodies. Changes in host cell tropism can affect recruitment of virus-specific CD8 T cells. Using mouse polyomavirus, we demonstrate that a single amino acid difference in VP1 known to shift viral tropism profoundly affects the quantity and quality of the anti-polyomavirus CD8 T cell response and its differentiation into memory cells. These findings raise the possibility that CD8 T cell responses to infections by human polyomaviruses may be influenced by VP1 mutations involving domains that engage host cell receptors.

scholarly journals Lymphocytoid Choriomeningitis Virus Activates Plasmacytoid Dendritic Cells and Induces a Cytotoxic T-Cell Response via MyD88

2007 ◽  
Vol 82 (1) ◽  
pp. 196-206 ◽  
Author(s):  
Andreas Jung ◽  
Hiroki Kato ◽  
Yutaro Kumagai ◽  
Himanshu Kumar ◽  
Taro Kawai ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Intracellular Signaling ◽  
Plasmacytoid Dendritic Cells ◽  
T Cell Response ◽  
Cytotoxic T Cell ◽  
Type I ◽  
Ctl Response ◽  
Type I Ifns ◽  
Lcmv Infection

ABSTRACTToll-like receptors (TLRs) and retinoic acid-inducible gene I-like helicases (RLHs) are two major machineries recognizing RNA virus infection of innate immune cells. Intracellular signaling for TLRs and RLHs is mediated by their cytoplasmic adaptors, i.e., MyD88 or TRIF and IPS-1, respectively. In the present study, we investigated the contributions of TLRs and RLHs to the cytotoxic T-lymphocyte (CTL) response by using lymphocytoid choriomeningitis virus (LCMV) as a model virus. The generation of virus-specific cytotoxic T lymphocytes was critically dependent on MyD88 but not on IPS-1. Type I interferons (IFNs) are known to be important for the development of the CTL response to LCMV infection. Serum levels of type I IFNs and proinflammatory cytokines were mainly dependent on the presence of MyD88, although IPS-1−/−mice showed a decrease in IFN-α levels but not in IFN-β and proinflammatory cytokine levels. Analysis ofIfna6+/GFPreporter mice revealed that plasmacytoid dendritic cells (DCs) are the major source of IFN-α in LCMV infection. MyD88−/−mice were highly susceptible to LCMV infection in vivo. These results suggest that recognition of LCMV by plasmacytoid DCs via TLRs is responsible for the production of type I IFNs in vivo. Furthermore, the activation of a MyD88-dependent innate mechanism induces a CTL response, which eventually leads to virus elimination.

Type I-IFNs interfere with GVH responses

Blood ◽  
2011 ◽  
Vol 118 (12) ◽  
pp. 3193-3194
Author(s):  
Pavan Reddy
Keyword(s):  
Type I ◽  
Type I Ifns

scholarly journals ICSBP-mediated immune protection against BCR-ABL–induced leukemia requires the CCL6 and CCL9 chemokines

Blood ◽  
2009 ◽  
Vol 113 (16) ◽  
pp. 3813-3820 ◽  
Author(s):  
Valentina Nardi ◽  
Olaia Naveiras ◽  
Mohammad Azam ◽  
George Q. Daley
Keyword(s):  
Murine Model ◽  
Consensus Sequence ◽  
Myelogenous Leukemia ◽  
Transformed Cells ◽  
Type I ◽  
Immune Protection ◽  
Immune Mechanism ◽  
Type I Ifns ◽  
New Strategies

Abstract Interferon (IFN) is effective at inducing complete remissions in patients with chronic myelogenous leukemia (CML), and evidence supports an immune mechanism. Here we show that the type I IFNs (alpha and beta) regulate expression of the IFN consensus sequence-binding protein (ICSBP) in BCR-ABL–transformed cells and as shown previously for ICSBP, induce a vaccine-like immunoprotective effect in a murine model of BCR-ABL–induced leukemia. We identify the chemokines CCL6 and CCL9 as genes prominently induced by the type I IFNs and ICSBP, and demonstrate that these immunomodulators are required for the immunoprotective effect of ICSBP expression. Insights into the role of these chemokines in the antileukemic response of IFNs suggest new strategies for immunotherapy of CML.

scholarly journals Activation of Stimulator of Interferon Genes (STING) and Sjögren Syndrome

2018 ◽  
Vol 97 (8) ◽  
pp. 893-900 ◽  
Author(s):  
J. Papinska ◽  
H. Bagavant ◽  
G.B. Gmyrek ◽  
M. Sroka ◽  
S. Tummala ◽  
...  
Keyword(s):  
Gene Expression ◽  
Viral Infections ◽  
Critical Role ◽  
Autoimmune Disorder ◽  
Sjögren Syndrome ◽  
Lymphoid Cells ◽  
Type I Interferons ◽  
Sjogren Syndrome ◽  
Type I ◽  
Type I Ifns

Sjögren syndrome (SS), a chronic autoimmune disorder causing dry mouth, adversely affects the overall oral health in patients. Activation of innate immune responses and excessive production of type I interferons (IFNs) play a critical role in the pathogenesis of this disorder. Recognition of nucleic acids by cytosolic nucleic acid sensors is a major trigger for the induction of type I IFNs. Upon activation, cytosolic DNA sensors can interact with the stimulator of interferon genes (STING) protein, and activation of STING causes increased expression of type I IFNs. The role of STING activation in SS is not known. In this study, to investigate whether the cytosolic DNA sensing pathway influences SS development, female C57BL/6 mice were injected with a STING agonist, dimethylxanthenone-4-acetic acid (DMXAA). Salivary glands (SGs) were studied for gene expression and inflammatory cell infiltration. SG function was evaluated by measuring pilocarpine-induced salivation. Sera were analyzed for cytokines and autoantibodies. Primary SG cells were used to study the expression and activation of STING. Our data show that systemic DMXAA treatment rapidly induced the expression of Ifnb1, Il6, and Tnfa in the SGs, and these cytokines were also elevated in circulation. In contrast, increased Ifng gene expression was dominantly detected in the SGs. The type I innate lymphoid cells present within the SGs were the major source of IFN-γ, and their numbers increased significantly within 3 d of treatment. STING expression in SGs was mainly observed in ductal and interstitial cells. In primary SG cells, DMXAA activated STING and induced IFN-β production. The DMXAA-treated mice developed autoantibodies, sialoadenitis, and glandular hypofunction. Our study demonstrates that activation of the STING pathway holds the potential to initiate SS. Thus, apart from viral infections, conditions that cause cellular perturbations and accumulation of host DNA within the cytosol should also be considered as possible triggers for SS.

An arms race: innate antiviral responses and counteracting viral strategies

2007 ◽  
Vol 35 (6) ◽  
pp. 1512-1514 ◽  
Author(s):  
M. Schröder ◽  
A.G. Bowie
Keyword(s):  
Nuclear Factor Κb ◽  
Signalling Pathways ◽  
Type I ◽  
Nuclear Factor ◽  
Regulatory Factor ◽  
Antiviral Responses ◽  
Type I Ifns ◽  
Activation Of Transcription ◽  
Molecular Patterns ◽  
Pro Inflammatory Cytokines

Viral recognition is mediated by different classes of PRRs (pattern-recognition receptors) among which the TLRs (Toll-like receptors) and the RLHs [RIG (retinoic-acid-inducible)-like helicases] play major roles. The detection of PAMPs (pathogen-associated molecular patterns) by these PRRs leads to the initiation of signalling pathways that ultimately result in the activation of transcription factors such as NF-κB (nuclear factor κB) and IRF-3 [IFN (interferon) regulatory factor-3] and IRF-7 and the induction of pro-inflammatory cytokines and type I IFNs. Viruses have evolved a fine-tuned mechanism to evade detection by the immune system or to interfere with the resulting signalling pathways. Here, we discuss viral evasion proteins that specifically interfere with TLR and/or RLH signalling.

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