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https://www.readbyqxmd.com/read/28822075/recycling-endosomes-in-human-cytotoxic-t-lymphocytes-constitute-an-auxiliary-intracellular-trafficking-pathway-for-newly-synthesized-perforin
#1
Kelsey Lesteberg, Jordan Orange, George Makedonas
Although cytotoxic T lymphocytes (CTLs) store perforin within cytoplasmic secretory granules for immediate use, perforin is synthesized anew within hours of TCR stimulation. Previously, we observed new perforin protein at an immunologic synapse independent of secretory lysosomes; herein, we aimed to determine how new perforin transits to the synapse if not via lytic granules. We analyzed antigen-specific human CTLs via imaging flow cytometry and high-resolution confocal microscopy, with attention to intracellular trafficking components and new perforin...
August 18, 2017: Immunologic Research
https://www.readbyqxmd.com/read/28819459/exosomes-derived-from-natural-killer-cells-exert-therapeutic-effect-in-melanoma
#2
Liya Zhu, Senthilkumar Kalimuthu, Prakash Gangadaran, Ji Min Oh, Ho Won Lee, Se Hwan Baek, Shin Young Jeong, Sang-Woo Lee, Jaetae Lee, Byeong-Cheol Ahn
Objective: Exosomes are nanovesicles that are released from normal and tumor cells and are detectable in cell culture supernatant and human biological fluids. Although previous studies have explored exosomes released from cancer cells, little is understood regarding the functions of exosomes released by normal cells. Natural killer (NK) cells display rapid immunity to metastatic or hematological malignancies, and efforts have been undertaken to clinically exploit the antitumor properties of NK cells. However, the characteristics and functions of exosomes derived from NK cells remain unknown...
2017: Theranostics
https://www.readbyqxmd.com/read/28819257/cytolytic-dna-vaccine-encoding-lytic-perforin-augments-the-maturation-of-and-antigen-presentation-by-dendritic-cells-in-a-time-dependent-manner
#3
Danushka K Wijesundara, Wenbo Yu, Ben J C Quah, Preethi Eldi, John D Hayball, Kerrilyn R Diener, Ilia Voskoboinik, Eric J Gowans, Branka Grubor-Bauk
The use of cost-effective vaccines capable of inducing robust CD8(+) T cell immunity will contribute significantly towards the elimination of persistent viral infections and cancers worldwide. We have previously reported that a cytolytic DNA vaccine encoding an immunogen and a truncated mouse perforin (PRF) protein significantly augments anti-viral T cell (including CD8(+) T cell) immunity. Thus, the current study investigated whether this vaccine enhances activation of dendritic cells (DCs) resulting in greater priming of CD8(+) T cell immunity...
August 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28811289/primary-tumors-limit-metastasis-formation-through-induction-of-il15-mediated-crosstalk-between-patrolling-monocytes-and-nk-cells
#4
Hiroshi Kubo, Sofia Mensurado, Natacha Goncalves-Sousa, Karine Serre, Bruno Silva-Santos
Metastases are responsible for the vast majority of cancer-related deaths. Although tumor cells can become invasive early during cancer progression, metastases formation typically occurs as a late event. How the immune response to primary tumors may dictate this outcome remains poorly understood, which hampers our capacity to manipulate it therapeutically. Here we used a two-step experimental model, based on the highly aggressive B16F10 melanoma, that temporally segregates the establishment of primary tumors (subcutaneously) and the formation of lung metastases (from intravenous injection)...
August 15, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28808112/regulation-of-perforin-activation-and-pre-synaptic-toxicity-through-c-terminal-glycosylation
#5
Imran G House, Colin M House, Amelia J Brennan, Omer Gilan, Mark A Dawson, James C Whisstock, Ruby Hp Law, Joseph A Trapani, Ilia Voskoboinik
Perforin is a highly cytotoxic pore-forming protein essential for immune surveillance by cytotoxic lymphocytes. Prior to delivery to target cells by exocytosis, perforin is stored in acidic secretory granules where it remains functionally inert. However, how cytotoxic lymphocytes remain protected from their own perforin prior to its export to secretory granules, particularly in the Ca(2+)-rich endoplasmic reticulum, remains unknown. Here, we show that N-linked glycosylation of the perforin C-terminus at Asn549 within the endoplasmic reticulum inhibits oligomerisation of perforin monomers and thus protects the host cell from premature pore formation...
August 14, 2017: EMBO Reports
https://www.readbyqxmd.com/read/28798777/mesenchymal-stem-cells-promote-metastasis-of-lung-cancer-cells-by-downregulating-systemic-antitumor-immune-response
#6
Marina Gazdic, Bojana Simovic Markovic, Nemanja Jovicic, Maja Misirkic-Marjanovic, Valentin Djonov, Vladimir Jakovljevic, Nebojsa Arsenijevic, Miodrag L Lukic, Vladislav Volarevic
Since majority of systemically administered mesenchymal stem cells (MSCs) become entrapped within the lungs, we used metastatic model of lung cancer, induced by intravenous injection of Lewis lung cancer 1 (LLC1) cells, to investigate the molecular mechanisms involved in MSC-mediated modulation of metastasis. MSCs significantly augmented lung cancer metastasis, attenuate concentrations of proinflammatory cytokines (TNF-α, IL-17), and increase levels of immunosuppressive IL-10, nitric oxide, and kynurenine in sera of LLC1-treated mice...
2017: Stem Cells International
https://www.readbyqxmd.com/read/28794456/activated-nk-cells-cause-placental-dysfunction-and-miscarriages-in-fetal-alloimmune-thrombocytopenia
#7
Issaka Yougbaré, Wei-She Tai, Darko Zdravic, Brigitta Elaine Oswald, Sean Lang, Guangheng Zhu, Howard Leong-Poi, Dawei Qu, Lisa Yu, Caroline Dunk, Jianhong Zhang, John G Sled, Stephen J Lye, Jelena Brkić, Chun Peng, Petter Höglund, B Anne Croy, S Lee Adamson, Xiao-Yan Wen, Duncan J Stewart, John Freedman, Heyu Ni
Miscarriage and intrauterine growth restriction (IUGR) are devastating complications in fetal/neonatal alloimmune thrombocytopenia (FNAIT). We previously reported the mechanisms for bleeding diatheses, but it is unknown whether placental, decidual immune cells or other abnormalities at the maternal-fetal interface contribute to FNAIT. Here we show that maternal immune responses to fetal platelet antigens cause miscarriage and IUGR that are associated with vascular and immune pathologies in murine FNAIT models...
August 9, 2017: Nature Communications
https://www.readbyqxmd.com/read/28771222/microrna-519a-3p-mediates-apoptosis-resistance-in-breast-cancer-cells-and-their-escape-from-recognition-by-natural-killer-cells
#8
Christian Breunig, Jens Pahl, Moritz Küblbeck, Matthias Miller, Daniela Antonelli, Nese Erdem, Cornelia Wirth, Rainer Will, Alexander Bott, Adelheid Cerwenka, Stefan Wiemann
Aggressive breast cancer is associated with poor patient outcome and characterized by the development of tumor cell variants that are able to escape from control of the immune system or are resistant to targeted therapies. The complex molecular mechanisms leading to immune escape and therapy resistance are incompletely understood. We have previously shown that high miR-519a-3p levels are associated with poor survival in breast cancer. Here, we demonstrate that miR-519a-3p confers resistance to apoptosis induced by TRAIL, FasL and granzyme B/perforin by interfering with apoptosis signaling in breast cancer cells...
August 3, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28769923/natural-killer-cells-from-patients-with-recombinase-activating-gene-and-non-homologous-end-joining-gene-defects-comprise-a-higher-frequency-of-cd56-bright-nkg2a-cells-and-yet-display-increased-degranulation-and-higher-perforin-content
#9
Kerry Dobbs, Giovanna Tabellini, Enrica Calzoni, Ornella Patrizi, Paula Martinez, Silvia Clara Giliani, Daniele Moratto, Waleed Al-Herz, Caterina Cancrini, Morton Cowan, Jacob Bleesing, Claire Booth, David Buchbinder, Siobhan O Burns, Talal A Chatila, Janet Chou, Vanessa Daza-Cajigal, Lisa M Ott de Bruin, MaiteTeresa de la Morena, Gigliola Di Matteo, Andrea Finocchi, Raif Geha, Rakesh K Goyal, Anthony Hayward, Steven Holland, Chiung-Hui Huang, Maria G Kanariou, Alejandra King, Blanka Kaplan, Anastasiya Kleva, Taco W Kuijpers, Bee Wah Lee, Vassilios Lougaris, Michel Massaad, Isabelle Meyts, Megan Morsheimer, Benedicte Neven, Sung-Yun Pai, Alessandro Plebani, Susan Prockop, Ismail Reisli, Jian Yi Soh, Raz Somech, Troy R Torgerson, Yae-Jaen Kim, Jolan E Walter, Andrew R Gennery, Sevgi Keles, John P Manis, Emanuela Marcenaro, Alessandro Moretta, Silvia Parolini, Luigi D Notarangelo
Mutations of the recombinase-activating genes 1 and 2 (RAG1 and RAG2) in humans are associated with a broad range of phenotypes. For patients with severe clinical presentation, hematopoietic stem cell transplantation (HSCT) represents the only curative treatment; however, high rates of graft failure and incomplete immune reconstitution have been observed, especially after unconditioned haploidentical transplantation. Studies in mice have shown that Rag(-/-) natural killer (NK) cells have a mature phenotype, reduced fitness, and increased cytotoxicity...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28757574/finding-a-balance-between-protection-and-pathology-the-dual-role-of-perforin-in-human-disease
#10
REVIEW
Robin C Willenbring, Aaron J Johnson
Perforin is critical for controlling viral infection and tumor surveillance. Clinically, mutations in perforin are viewed as unfavorable, as lack of this pore-forming protein results in lethal, childhood disease, familial hemophagocytic lymphohistiocytosis type 2 (FHL 2). However, many mutations in the coding region of PRF1 are not yet associated with disease. Animal models of viral-associated blood-brain barrier (BBB) disruption and experimental cerebral malaria (ECM) have identified perforin as critical for inducing pathologic central nervous system CNS vascular permeability...
July 25, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28757431/perforin-a-key-shaped-weapon-in-the-immunological-arsenal
#11
REVIEW
Bradley A Spicer, Paul J Conroy, Ruby H P Law, Ilia Voskoboinik, James C Whisstock
Cytotoxic lymphocytes play a key role in immune homeostasis through elimination of virally-infected and transformed target cells. They do this by employing the potent pore-forming protein, perforin, a molecule that permits cytotoxic proteases such as granzyme B to enter the target cell cytoplasm. The synergistic activities of perforin and granzymes bring about the destruction of target cells in a process that is now more clearly understood as a result of structural and cellular biology. These data are helping the development of new classes of immunosuppressive molecules for use in treating immune driven disease and in enhancing the success of transplant therapies...
July 27, 2017: Seminars in Cell & Developmental Biology
https://www.readbyqxmd.com/read/28747084/mir-615-5p-depresses-natural-killer-cells-cytotoxicity-through-repressing-igf-1r-in-hepatocellular-carcinoma-patients
#12
Mai Atef Rahmoon, Rana Ahmed Youness, Asmaa Ibrahim Gomaa, Mohamed Tarif Hamza, Imam Waked, Hend Mohamed El Tayebi, Ahmed Ihab Abdelaziz
miR-615-5p was characterized by our group as a tumour suppressor. IGF-1 R activates a downstream signalling pathway, well characterized in liver cells, however, its role in immunity especially Natural Killer cells (NKs) remains vague. This study aimed at investigating the regulatory role of miR-615-5p on IGF signalling and its impact on NKs cytotoxicity in HCC. Our results showed an upregulation in miR-615-5p and IGF-1 R in NKs of 130 HCC patients compared to 35 controls. Forcing the expression of miR-615-5p, repressed IGF-IR, attenuated NKs cytotoxicity, decreased CD56(dim), increased CD56(bright) NK subsets and reduced the cytotoxic markers NKG2D, TNF-α and perforins...
July 27, 2017: Growth Factors
https://www.readbyqxmd.com/read/28743062/peripheral-leucocytes-and-tissue-gene-expression-of-granzyme-b-perforin-system-and-serpinb9-impact-on-inflammation-and-insulin-resistance-in-coronary-atherosclerosis
#13
Eman F Sanad, Nadia M Hamdy, Adel K El-Etriby, Samer A Sebak, Hala O El-Mesallamy
AIM: The imbalance between proapoptotic granzyme B (GZB)/perforin (PRF) system and proteinase inhibitor-9 (PI-9; serpinB9); the only known inhibitor of human GZB, has been demonstrated in atherosclerosis. However, their role in atherosclerosis with the impact of type 2 diabetes mellitus (DM) as well as their contribution to hallmarks of atherosclerosis is not clear. SUBJECTS AND METHODS: ELISA for serum insulin, high sensitivity C-reactive protein (hsCRP) and GZB levels in atherosclerotic coronary artery diseases (CAD) patients were estimated in comparison to apparently healthy controls, while GZB, PRF and PI-9 mRNA expression levels were quantified by Taqman RT-PCR in both peripheral leucocytes and atherosclerotic tissues...
July 12, 2017: Diabetes Research and Clinical Practice
https://www.readbyqxmd.com/read/28741159/sebaceous-gland-carcinoma-of-the-ocular-adnexa-variability-in-clinical-and-histological-appearance-with-analysis-of-immunohistochemical-staining-patterns
#14
Eva Janine Schmitz, Martina C Herwig-Carl, Frank G Holz, Karin U Loeffler
PURPOSE: The purpose of the study was to evaluate the characteristics of sebaceous gland carcinoma (SGC) of the ocular adnexae, which is due to a high variability in clinical, histological and immunohistochemical characteristics often challenging to diagnose. METHODS: Records of six patients with SGC were reviewed, who underwent surgical excision and who were histologically diagnosed with SGC. For comparison, there were specimens from four patients with basal cell carcinoma (BCC) and four patients with squamous cell carcinoma (SCC)...
July 24, 2017: Graefe's Archive for Clinical and Experimental Ophthalmology
https://www.readbyqxmd.com/read/28733576/mait-cells-accumulate-in-placental-intervillous-space-and-display-a-highly-cytotoxic-phenotype-upon-bacterial-stimulation
#15
Martin Solders, Laia Gorchs, Tom Erkers, Anna-Carin Lundell, Silvia Nava, Sebastian Gidlöf, Eleonor Tiblad, Isabelle Magalhaes, Helen Kaipe
During pregnancy, the maternal immune system must tolerate the developing foetus, and yet retain a potent antimicrobial response to prevent infections. Mucosal associated invariant T (MAIT) cells recognize microbial-derived vitamin B metabolites presented on the MR1 molecule, but their presence and function at the foetal-maternal interface is not known. We here isolated mononuclear cells from paired samples of peripheral blood (PB), intervillous blood (IVB), and decidua parietalis (DP) following uncomplicated term pregnancies...
July 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28718416/the-untold-story-of-granzymes-in-oncoimmunology-novel-opportunities-with-old-acquaintances
#16
REVIEW
Maykel Arias, Luis Martínez-Lostao, Llipsy Santiago, Angel Ferrandez, David J Granville, Julián Pardo
For more than 20 years perforin and granzymes (GZMs) have been recognized as key cell death executors of cytotoxic T (Tc) and natural killer (NK) cells during cancer immunosurveillance. In immune surveillance, perforin and GZMB, the most potent cytotoxic molecules, act mainly as antitumoral and anti-infectious factors. However, when expressed by immune regulatory cells they may contribute to immune evasion of specific cancer types. By contrast, the other major granzyme, GZMA, seems not to play a major role in Tc/NK cell-mediated cytotoxicity, but acts as a proinflammatory cytokine that might contribute to cancer development...
June 2017: Trends in Cancer
https://www.readbyqxmd.com/read/28717654/fusion-to-flaviviral-leader-peptide-targets-hiv-1-reverse-transcriptase-for-secretion-and-reduces-its-enzymatic-activity-and-ability-to-induce-oxidative-stress-but-has-no-major-effects-on-its-immunogenic-performance-in-dna-immunized-mice
#17
Anastasia Latanova, Stefan Petkov, Yulia Kuzmenko, Athina Kilpeläinen, Alexander Ivanov, Olga Smirnova, Olga Krotova, Sergey Korolev, Jorma Hinkula, Vadim Karpov, Maria Isaguliants, Elizaveta Starodubova
Reverse transcriptase (RT) is a key enzyme in viral replication and susceptibility to ART and a crucial target of immunotherapy against drug-resistant HIV-1. RT induces oxidative stress which undermines the attempts to make it immunogenic. We hypothesized that artificial secretion may reduce the stress and make RT more immunogenic. Inactivated multidrug-resistant RT (RT1.14opt-in) was N-terminally fused to the signal providing secretion of NS1 protein of TBEV (Ld) generating optimized inactivated Ld-carrying enzyme RT1...
2017: Journal of Immunology Research
https://www.readbyqxmd.com/read/28713379/op9-feeder-cells-are-superior-to-m2-10b4-cells-for-the-generation-of-mature-and-functional-natural-killer-cells-from-umbilical-cord-hematopoietic-progenitors
#18
Lara Herrera, Juan Manuel Salcedo, Silvia Santos, Miguel Ángel Vesga, Francisco Borrego, Cristina Eguizabal
Adoptive natural killer (NK) cell therapy relies on the acquisition of large numbers of mature and functional NK cells. An option for future immunotherapy treatments is to use large amounts of NK cells derived and differentiated from umbilical cord blood (UCB) CD34(+) hematopoietic stem cells (HSCs), mainly because UCB is one of the most accessible HSC sources. In our study, we compared the potential of two stromal cell lines, OP9 and M2-10B4, for in vitro generation of mature and functional CD56(+) NK cells from UCB CD34(+) HSC...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28705375/regulation-of-expression-and-trafficking-of-perforin-2-by-lps-and-tnf-%C3%AE
#19
Peng Xiong, Motoaki Shiratsuchi, Takamitsu Matsushima, Jiyuan Liao, Emi Tanaka, Yasuhiro Nakashima, Ryoichi Takayanagi, Yoshihiro Ogawa
Perforin-2 is constitutively expressed in macrophages that are required for bacterial control. In this study, we found that perforin-2 is expressed in human macrophages with two isoforms: full-length perforin-2a and a splice variant, perforin-2b. Two isoforms show different subcellular distributions. Perforin-2a was predominantly localized to the membrane of endosome-like vesicles by a C-terminal transmembrane domain. In contrast, the short isoform perforin-2b lacking the transmembrane domain failed to localize to the membrane of vesicles...
July 8, 2017: Cellular Immunology
https://www.readbyqxmd.com/read/28694809/unperturbed-cytotoxic-lymphocyte-phenotype-and-function-in-myalgic-encephalomyelitis-chronic-fatigue-syndrome-patients
#20
Jakob Theorell, Indre Bileviciute-Ljungar, Bianca Tesi, Heinrich Schlums, Mette Sophie Johnsgaard, Babak Asadi-Azarbaijani, Elin Bolle Strand, Yenan T Bryceson
Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) is a debilitating disorder linked to diverse intracellular infections as well as physiological stress. Cytotoxic lymphocytes combat intracellular infections. Their function is attenuated by stress. Despite numerous studies, the role of cytotoxic lymphocytes in ME/CFS remains unclear. Prompted by advances in the understanding of defects in lymphocyte cytotoxicity, the discovery of adaptive natural killer (NK) cell subsets associated with certain viral infections, and compelling links between stress, adrenaline, and cytotoxic lymphocyte function, we reassessed the role of cytotoxic lymphocytes in ME/CFS...
2017: Frontiers in Immunology
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