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IFN-γ signaling

Shu Lian, Ruizhi Xie, Yuying Ye, Xiaodong Xie, Shuhui Li, Yusheng Lu, Bifei Li, Yunlong Cheng, Vladimir L Katanaev, Lee Jia
BACKGROUND: Treatment multiple tumors by immune therapy can be achieved by mobilizing both innate and adaptive immunity. The programmed death ligand 1 (PD-L1; or CD274, B7-H1) is a critical "don't find me" signal to the adaptive immune system. Equally CD47 is a critical "don't eat me" signal to the innate immune system and a regulator of the adaptive immune response. METHOD: Both of CD47 and PD-L1 are overexpressed on the surface of cancer cells to enable to escape immune-surveillance...
March 14, 2019: EBioMedicine
Edward C So, Ariana Khaladj-Ghom, Yaping Ji, Julian Amin, Yang Song, Erin Burch, Hua Zhou, Haoping Sun, Shaodong Chen, Soren Bentzen, Ronna Hertzano, Xiaoyu Zhang, Scott E Strome
Given the heightened interest in manipulation of co-signaling cascades for cancer immunotherapy, we sought to determine how/whether tumors decorated with therapeutic monoclonal antibodies (mAbs) impact the expression of co-signaling molecules on human NK cells. Stimulation of NK cells with aggregated IgG1 resulted in the upregulation of HAVCR2 - the gene encoding T-cell immunoglobulin and mucin-containing domain (Tim)-3 - known to be involved in the induction of peripheral T cell tolerance. This upregulation of HAVCR2 was recapitulated at the protein level, following NK cell stimulation by either mAb opsonized tumors, recombinant human IgG1 Fc multimer, and/or non-Fc stimuli e...
March 2, 2019: Immunobiology
Rosa Sottile, Giorgia Federico, Cinzia Garofalo, Rossana Tallerico, Maria Concetta Faniello, Barbara Quaresima, Costanza Maria Cristiani, Maddalena Di Sanzo, Gianni Cuda, Valeria Ventura, Arnika Kathleen Wagner, Gianluca Contrò, Nicola Perrotti, Elio Gulletta, Soldano Ferrone, Klas Kärre, Francesco Saverio Costanzo, Francesca Carlomagno, Ennio Carbone
The ability of pathogens to sequester iron from their host cells and proteins affects their virulence. Moreover, iron is required for various innate host defense mechanisms as well as for acquired immune responses. Therefore, intracellular iron concentration may influence the interplay between pathogens and immune system. Here, we investigated whether changes in iron concentrations and intracellular ferritin heavy chain (FTH) abundance may modulate the expression of Major Histocompatibility Complex molecules (MHC), and susceptibility to Natural Killer (NK) cell cytotoxicity...
2019: Frontiers in Immunology
Mohammed Alosaimi, Manfred Hoenig, Faris Jaber, Craig D Platt, Jennifer Jones, Jacqueline Wallace, Klaus-Michael Debatin, Ansgar Schulz, Eva Jacobsen, Peter Möller, Hanan E Shamseldin, Ferdous Abdulwahab, Niema Ibrahim, Hosam Alardati, Faisal Almuhizi, Ibraheem F Abosoudah, Talal A Basha, Janet Chou, Fowzan S Alkuraya, Raif S Geha
BACKGROUND: The tumor necrosis family factor receptor (TNFR) family member 4-1BB (CD137) is encoded by TNFRSF9 and expressed on activated T cells. 4-1BB provides a co-stimulatory signal that enhances CD8+ T cell survival, cytotoxicity, and mitochondrial activity, thereby promoting immunity against viruses and tumors. The ligand for 4-1BB (4-1BBL) is expressed on antigen-presenting cells and Epstein-Barr virus (EBV) transformed B cells. OBJECTIVE: We investigated the genetic basis of recurrent sino-pulmonary infections, persistent EBV viremia, and EBV-induced lymphoproliferation in two unrelated patients...
March 11, 2019: Journal of Allergy and Clinical Immunology
Yifan Li, Chujun Zhao, Jiajing Liu, Zhou Lu, Mingfang Lu, Jie Gu, Ronghua Liu
Dendritic cells (DCs), as professional antigen‑presenting cells are essential for the initial activation of adaptive antitumor immunity. CD1d is considered to present phospholipid and glycosphingolipid antigens to NKT cells. However, it is currently unknown whether CD1d expression on DCs is capable of enhancing antitumor immunity, particularly T‑cell related immunity. We observed that CD1d was predominantly expressed on DCs in 3LL tumor‑bearing mice, whilst a deficiency of CD1d promoted tumor growth. Notably, CD1d expression on DCs was not only required for presenting antigen to NKT cells, but also markedly promoted CD4+T and CD8+T cell activation, particularly cytotoxic T cells...
February 28, 2019: Oncology Reports
Hongmei Fu, Maryam Jangani, Aleesha Parmar, Guosu Wang, David Coe, Sarah Spear, Inga Sandrock, Melania Capasso, Mark Coles, Georgina Cornish, Helena Helmby, Federica M Marelli-Berg
Protective immunity relies upon differentiation of T cells into the appropriate subtype required to clear infections and efficient effector T cell localization to antigen-rich tissue. Recent studies have highlighted the role played by subpopulations of tissue-resident memory (TRM ) T lymphocytes in the protection from invading pathogens. The intestinal mucosa and associated lymphoid tissue are densely populated by a variety of resident lymphocyte populations, including αβ and γδ CD8+ intraepithelial T lymphocytes (IELs) and CD4+ T cells...
2019: Frontiers in Immunology
Nicole E Behrens, Peter N Lipke, Darrell Pilling, Richard H Gomer, Stephen A Klotz
In patients with invasive fungal diseases, there is often little cellular inflammatory response. We tested the idea that binding of the human constitutive plasma protein serum amyloid P component (SAP) (also called PTX2) to Candida albicans dampens the innate immune response to this fungus. Many pathogenic fungi have cell surface amyloid-like structures important for adhesion and biofilm formation. Human SAP bound to fungi that expressed functional cell surface amyloid, but SAP had minimal binding to fungi with reduced expression of cell surface amyloid...
March 12, 2019: MBio
Daniel S Green, Syed R Husain, Chase L Johnson, Yuki Sato, Jing Han, Bharat Joshi, Stephen M Hewitt, Raj K Puri, Kathryn C Zoon
AIM:  We have shown that IL-4 fused to Pseudomonas exotoxin (IL-4-PE) is cytotoxic to ovarian cancer cell lines. The antineoplastic properties of IFN-α, IFN-γ and IL-4-PE have been studied and showed some promise in the clinical trials. Here, we investigated whether the combination of IL-4-PE, IFN-α and IFN-γ will result in increased ovarian cancer cell death in vitro and in vivo. MATERIALS & METHODS: Ovarian cancer cells were tested in vitro to analyze the cytotoxic effects of IL-4-PE, IFN-α and IFN-γ, and the combination of all three...
April 2019: Immunotherapy
Haibo Su, Baozhou Peng, Zhen Zhang, Zijian Liu, Zhi Zhang
The myobacterial factors and the associated mechanism by which Mycobacterium tuberculosis (Mtb) evades the host immune surveillance system remain widely unexplored. Here, we found that overexpressing Rv1016c, a mannosylated protein of M. tuberculosis in BCG (rBCG-Rv1016c) led to increased virulence of the recombined BCG in the severe-combined immunodeficient (SCID) mice model and to a loss of protective efficacy in a zebrafish-M. marinum model, compared to wild type BCG. Further investigations on the effects of rBCG-Rv1016c on the host innate immunity revealed that rBCG-Rv1016c decreased the production of cytokines IL-2, IL-12p70, TGF-β, IL-6 as well as of the co-stimulatory molecules CD80, CD86, MHC-I and MHC-II by the infected DCs...
March 8, 2019: Molecular Immunology
Wivine Burny, Arnaud Marchant, Caroline Hervé, Andrea Callegaro, Magalie Caubet, Laurence Fissette, Lien Gheyle, Catherine Legrand, Cheikh Ndour, Fernanda Tavares Da Silva, Robbert van der Most, Fabienne Willems, Arnaud M Didierlaurent, Juan Yarzabal
BACKGROUND: Adjuvants like AS01B increase the immunogenicity of vaccines and generally cause increased transient reactogenicity compared with Alum. A phase II randomized trial was conducted to characterize the response to AS01B and Alum adjuvanted vaccines. A post-hoc analysis was performed to examine the associations between reactogenicity and innate immune parameters. METHODS: The trial involved 60 hepatitis B-naïve adults aged 18-45 years randomized 1:1 to receive either two doses of HBsAg-AS01B on Day (D)0 and D30, or three doses of HBsAg-Alum on D0, D30, D180...
March 5, 2019: Vaccine
Caleb D Swaim, Larissa A Canadeo, Jon M Huibregtse
ISG15 is a ubiquitin-like protein (Ubl) that is expressed in response to Type 1 Interferon (IFN-α/β) signaling. Remarkably, ISG15 has three distinct biochemical activities involved in innate immune responses to viral and/or microbial infections. The canonical function of ISG15 is as a posttranslational modifier, and protein ISGylation has been demonstrated to be antiviral. A second intracellular function, independent of conjugation activity, is attenuation of IFN-α/β signaling at the interferon receptor, which appears to be important for terminating IFN responses...
2019: Methods in Enzymology
Hideyuki Higashi, Takashi Maejima, Lang Ho Lee, Yukiyoshi Yamazaki, Michael O Hottiger, Sasha A Singh, Masanori Aikawa
ADP-ribosylation is a post-translational modification that, until recently, has remained elusive to study at the cellular level. Previously dependent on radioactive tracers to identify ADP-ribosylation targets, several advances in mass spectrometric workflows now permit global identification of ADP-ribosylated substrates. In this study, we capitalized on two ADP-ribosylation enrichment strategies, and multiple activation methods performed on the Orbitrap Fusion Lumos, to identify IFN-γ-induced ADP-ribosylation substrates in macrophages...
March 8, 2019: Journal of Proteome Research
Yu-Long Xue, Sheng-Xiao Zhang, Chao-Feng Zheng, Yu-Feng Li, Li-Hui Zhang, Yu-Fei Hao, Shu Wang, Xue-Wen Li
Signal transducer and activator of transcription 4 (STAT4) has been implicated in the progression of myocarditis. The aim of the current study was to investigate the role by which STAT4 influences autoimmune myocarditis in an attempt to identify a theoretical therapeutic perspective for the condition. After successful establishment of an autoimmune myocarditis rat model, the expression patterns of STAT4, NF-κB pathway-related genes, Th1 inflammatory cytokines (IFN-γ and IL-2), and Th2 inflammatory cytokines (IL-6 and IL-10) were subsequently determined...
March 8, 2019: Inflammation
Lin Cheng, Xian Tang, Liumei Xu, Lukun Zhang, Huichun Shi, Qiaoli Peng, Fang Zhao, Yang Zhou, Yun He, Hui Wang, Boping Zhou, Zhiliang Gao, Zhiwei Chen
BACKGROUND: We recently identified a novel alternatively spliced isoform of human programmed cell death 1 (PD-1), named Δ42PD1, which contains a 42-base-pair in-frame deletion compared with the full-length PD-1. Δ42PD1 is likely constitutively expressed on human monocytes and down-regulated in patients infected with human immunodeficiency virus type 1 (HIV-1). The mechanism underlying the regulation of Δ42PD-1 expression in monocytes remains unknown. METHODS: By flow cytometry, we investigated the effect of Interferon-gamma (INF-γ) on the expression of Δ42PD1 in primary human monocytes as well as monocytic cell lines THP-1 and U937 cells...
February 21, 2019: Immunobiology
Shengchuan Huang, Yan Pan, Qingdong Zhang, Weiping Sun
BACKGROUND In this study, we assessed the role of CD200 and CD200 receptor (CD200R) in regulating CD4+T cell subsets and assessed the therapeutic efficacy of thermal ablation for liver hepatocellular carcinoma (HCC) in rats. MATERIAL AND METHODS Seventy-eight male C57BL/6 rats were randomly divided into 7 groups: a control group, a model group, a CD200FC group, an anti-CD200R1 mAb group, a thermal ablation group, a thermal ablation+CD200 FC group, and a thermal ablation+anti-CD200R1 mAb group. The levels of CD200, CD200R1, Th1, Th17, and Treg in peripheral blood were detected by flow cytometry...
March 6, 2019: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
Ke-Yue Ma, Alexandra A Schonnesen, Amy Brock, Carla Van Den Berg, S Gail Eckhardt, Zhihua Liu, Ning Jiang
Immunotherapy has emerged as a promising approach to treat cancer. However, partial responses across multiple clinical trials support the significance of characterizing intertumor and intratumor heterogeneity to achieve better clinical results and as potential tools in selecting patients for different types of cancer immunotherapies. Yet, the type of heterogeneity that informs clinical outcome and patient selection has not been fully explored. In particular, the lack of characterization of immune response-related genes in cancer cells hinders the further development of metrics to select and optimize immunotherapy...
February 21, 2019: JCI Insight
Hyun Jin Park, Gun-Young Jang, Young Seob Kim, Jung Hwa Park, Sung Eun Lee, Manh-Cuong Vo, Je-Jung Lee, Hee Dong Han, In Duk Jung, Tae Heung Kang, Yeong-Min Park
BACKGROUND: Dendritic cells (DCs) are professional antigen presenting cells (APCs), which can activate antigen-specific CD8+ T cell immunity, resulting in tumor clearance. Immature DCs are usually stimulated by various adjuvants through their immune receptors. Among them, Toll-like receptor 4 (TLR4) has an important role in activating DCs to cause their maturation. In fact, TLR4 is well-known to induce innate and adaptive immune responses against various external microbial or internal damage associated molecular patterns (DAMP)...
February 28, 2019: Journal for Immunotherapy of Cancer
Shahram Solaymani-Mohammadi, Jay A Berzofsky
The mucosal surface of the intestinal tract represents a major entry route for many microbes. Despite recent progress in the understanding of the IL-21/IL-21R signaling axis in the generation of germinal center B cells, the roles played by this signaling pathway in the context of enteric microbial infections is not well-understood. Here, we demonstrate that Il21r-/- mice are more susceptible to colonic microbial infection, and in the process discovered that the IL-21/IL-21R signaling axis surprisingly collaborate with the IFN-γ/IFN-γR signaling pathway to enhance the expression of interferon-stimulated genes (ISGs) required for protection, via amplifying activation of STAT1 in mucosal CD4+ T cells in a murine model of Citrobacter rodentium colitis...
February 28, 2019: PLoS Pathogens
Tianle Gu, Dandan Yu, Yu Fan, Yong Wu, Yu-Lin Yao, Ling Xu, Yong-Gang Yao
Following viral detection and interferons (IFNs) production, several hundreds of IFN-stimulated genes (ISGs) are subsequently induced to act as direct antiviral effectors or regulators of the IFN signaling. The guanylate-binding protein (GBP) family belongs to IFN-inducible GTPases defending the host against a diverse group of invading pathogens such as parasites, bacteria and viruses. The Chinese tree shrew (Tupaia belangeri chinese) has been increasingly used as an alternative experimental animal to primates in studying viral infectious diseases...
February 25, 2019: Developmental and Comparative Immunology
Yu Pang, Zhaoxia Zhang, Yuntong Chen, Shinuo Cao, Xiuqin Yang, Honglin Jia
Reactive oxygen species (ROS) produced by oxidases and non-enzymatic sources are important for host defense against intracellular pathogens. In this study, we knocked out the Nrf2 gene in RAW264.7 cells using the CRISPR/Cas9 system and investigated the antioxidant effects of the Nrf2 pathway in the cells stimulated by IFN-γ and TNF-α. The results indicated that the Nrf2 signaling pathway is necessary for maintaining redox homeostasis in activated RAW264.7 cells. Inactivation of Nrf2 impaired parasite growth...
February 27, 2019: Parasite Immunology
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