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https://www.readbyqxmd.com/read/27907215/cd8-t-cells-induce-fatal-brainstem-pathology-during-cerebral-malaria-via-luminal-antigen-specific-engagement-of-brain-vasculature
#1
Phillip A Swanson, Geoffrey T Hart, Matthew V Russo, Debasis Nayak, Takele Yazew, Mirna Peña, Shahid M Khan, Chris J Janse, Susan K Pierce, Dorian B McGavern
Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection that results in thousands of deaths each year, mostly in African children. The in vivo mechanisms underlying this fatal condition are not entirely understood. Using the animal model of experimental cerebral malaria (ECM), we sought mechanistic insights into the pathogenesis of CM. Fatal disease was associated with alterations in tight junction proteins, vascular breakdown in the meninges / parenchyma, edema, and ultimately neuronal cell death in the brainstem, which is consistent with cerebral herniation as a cause of death...
December 2016: PLoS Pathogens
https://www.readbyqxmd.com/read/27906544/lfa-1-icam-1-interaction-as-a-therapeutic-target-in-dry-eye-disease
#2
Stephen C Pflugfelder, Michael Stern, Steven Zhang, Amir Shojaei
Dry eye disease (DED) is a common ocular disorder associated with inflammation of the lacrimal gland and ocular surface. The interaction of the integrin lymphocyte function-associated antigen-1 (LFA-1) with its cognate ligand intercellular adhesion molecule-1 (ICAM-1) is known to have important roles in the interaction of a variety of cells involved in immune responses and inflammation, including those prominent in ocular surface inflammation. Lifitegrast, an LFA-1 antagonist that blocks binding of ICAM-1 to LFA-1, has recently been approved in the United States for the treatment of signs and symptoms of DED...
December 1, 2016: Journal of Ocular Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/27888551/selective-targeting-of-high-affinity-lfa-1-does-not-augment-costimulation-blockade-in-a-nonhuman-primate-renal-transplantation-model
#3
K P Samy, D A Anderson, D J Lo, M S Mulvihill, M Song, A B Farris, B S Parker, A L MacDonald, C Lu, T A Springer, S C Kachlany, K A Reimann, T How, F V Leopardi, K S Franke, K D Williams, B H Collins, A D Kirk
Costimulation blockade (CoB) via belatacept is a lower morbidity alternative to calcineurin inhibitor (CNI)-based immunosuppression. However, it has higher rates of early acute rejection. These early rejections are mediated in part by memory T cells, which have reduced dependence on the pathway targeted by belatacept, and increased adhesion molecule expression. One such molecule is Leukocyte Function Associated Antigen (LFA)-1. LFA-1 exists in two forms, a commonly expressed, low-affinity form, and a transient, high-affinity form, expressed only during activation...
November 26, 2016: American Journal of Transplantation
https://www.readbyqxmd.com/read/27883115/lifitegrast-first-lfa-1-icam-1-antagonist-for-treatment-of-dry-eye-disease
#4
D M Paton
Dry eye disease is an extremely common condition affecting millions worldwide. The underlying pathophysiological mechanism is thought to be localized inflammation of the ocular surface resulting in the localization of T cells at this surface followed by their activation and subsequent liberation of cytokines. This effect on T cells results from the binding of lymphocyte function-associated antigen-1 (LFA-1) located on T cells to intercellular adhesion molecule 1 (ICAM-1) expressed on inflamed epithelium and endothelium, and on T cells...
September 2016: Drugs of Today
https://www.readbyqxmd.com/read/27844285/th17-cells-induce-dopaminergic-neuronal-death-via-lfa-1-icam-1-interaction-in-a-mouse-model-of-parkinson-s-disease
#5
Zhan Liu, Yan Huang, Bei-Bei Cao, Yi-Hua Qiu, Yu-Ping Peng
T helper (Th)17 cells, a subset of CD4(+) T lymphocytes, have strong pro-inflammatory property and appear to be essential in the pathogenesis of many inflammatory diseases. However, the involvement of Th17 cells in Parkinson's disease (PD) that is characterized by a progressive degeneration of dopaminergic (DAergic) neurons in the nigrostriatal system is unclear. Here, we aimed to demonstrate that Th17 cells infiltrate into the brain parenchyma and induce neuroinflammation and DAergic neuronal death in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)- or 1-methyl-4-phenylpyridinium (MPP(+))-induced PD models...
November 14, 2016: Molecular Neurobiology
https://www.readbyqxmd.com/read/27825159/injection-of-htert-transduced-endothelial-progenitor-cells-promotes-beneficial-aortic-changes-in-a-high-fat-dietary-model-of-early-atherosclerosis
#6
Xingsheng Li, Yanru Deng, Shunrong Zhao, Dandan Zhang, Qingwei Chen
OBJECTIVES: Cultured endothelial progenitor cells (EPCs) display troubling issues that adversely affect their applicability to endothelial regeneration. We hypothesized that transduction of the human telomerase catalytic subunit (hTERT) gene would enhance EPC function in treating dietary-induced early atherosclerosis (AS). METHODS: A dietary-induced early AS model was successfully constructed in 90 healthy male rats, while 30 healthy control (HC) rats were normally fed...
November 9, 2016: Cardiology
https://www.readbyqxmd.com/read/27799367/formin-generated-actomyosin-arcs-propel-t-cell-receptor-microcluster-movement-at-the-immune-synapse
#7
Sricharan Murugesan, Jinsung Hong, Jason Yi, Dong Li, Jordan R Beach, Lin Shao, John Meinhardt, Grey Madison, Xufeng Wu, Eric Betzig, John A Hammer
Actin assembly and inward flow in the plane of the immunological synapse (IS) drives the centralization of T cell receptor microclusters (TCR MCs) and the integrin leukocyte functional antigen 1 (LFA-1). Using structured-illumination microscopy (SIM), we show that actin arcs populating the medial, lamella-like region of the IS arise from linear actin filaments generated by one or more formins present at the IS distal edge. After traversing the outer, Arp2/3-generated, lamellipodia-like region of the IS, these linear filaments are organized by myosin II into antiparallel concentric arcs...
November 7, 2016: Journal of Cell Biology
https://www.readbyqxmd.com/read/27760339/the-integrin-lfa-1-controls-t-follicular-helper-cell-generation-and-maintenance
#8
Alexandre P Meli, Ghislaine Fontés, Danielle T Avery, Scott A Leddon, Mifong Tam, Michael Elliot, Andre Ballesteros-Tato, Jim Miller, Mary M Stevenson, Deborah J Fowell, Stuart G Tangye, Irah L King
T follicular helper (Tfh) cells are a CD4(+) T cell subset critical for long-lived humoral immunity. We hypothesized that integrins play a decisive role in Tfh cell biology. Here we show that Tfh cells expressed a highly active form of leukocyte function-associated antigen-1 (LFA-1) that was required for their survival within the germinal center niche. In addition, LFA-1 promoted expression of Bcl-6, a transcriptional repressor critical for Tfh cell differentiation, and inhibition of LFA-1 abolished Tfh cell generation and prevented protective humoral immunity to intestinal helminth infection...
October 18, 2016: Immunity
https://www.readbyqxmd.com/read/27721490/coordinated-integrin-activation-by-actin-dependent-force-during-t-cell-migration
#9
Pontus Nordenfelt, Hunter L Elliott, Timothy A Springer
For a cell to move forward it must convert chemical energy into mechanical propulsion. Force produced by actin polymerization can generate traction across the plasma membrane by transmission through integrins to their ligands. However, the role this force plays in integrin activation is unknown. Here we show that integrin activity and cytoskeletal dynamics are reciprocally linked, where actin-dependent force itself appears to regulate integrin activity. We generated fluorescent tension-sensing constructs of integrin αLβ2 (LFA-1) to visualize intramolecular tension during cell migration...
October 10, 2016: Nature Communications
https://www.readbyqxmd.com/read/27720134/l-plastin-regulates-the-stability-of-the-immune-synapse-of-naive-and-effector-t-cells
#10
Guido Wabnitz, Emre Balta, Yvonne Samstag
T-cells need to be tightly regulated during their activation and effector phase to assure an appropriate defence against cancer or pathogens and - vice versa - to avoid autoimmune reactions. Regulatory signals are provided via the immune synapse between T-cells and antigen-presenting cells (APCs) or target cells. The stability and kinetics of immune synapse formation is critical for proper T-cell functions. It requires dynamic rearrangements of the actin cytoskeleton necessary for organized spatio-temporal redistribution of receptors and adhesion molecules...
September 27, 2016: Advances in Biological Regulation
https://www.readbyqxmd.com/read/27716898/distinct-patterns-of-cytolytic-t-cell-activation-by-different-tumour-cells-revealed-by-ca-2-signalling-and-granule-mobilization
#11
Melissa Frick, Pierre Mouchacca, Grégory Verdeil, Yannick Hamon, Cyrille Billaudeau, Michel Buferne, Mathieu Fallet, Nathalie Auphan-Anezin, Anne-Marie Schmitt-Verhulst, Claude Boyer
Cancer-germline genes in both humans and mice have been shown to encode antigens susceptible to targeting by cytotoxic CD8 T effector cells (CTL). We analysed the ability of CTL to kill different tumour cell lines expressing the same cancer-germline gene P1A (Trap1a). We previously demonstrated that CTL expressing a T-cell receptor specific for the P1A35-43 peptide associated with H-2L(d) , although able to induce regression of P1A-expressing P815 mastocytoma cells, were much less effective against P1A-expressing melanoma cells...
October 7, 2016: Immunology
https://www.readbyqxmd.com/read/27703233/biomimetic-carriers-mimicking-leukocyte-plasma-membrane-to-increase-tumor-vasculature-permeability
#12
R Palomba, A Parodi, M Evangelopoulos, S Acciardo, C Corbo, E de Rosa, I K Yazdi, S Scaria, R Molinaro, N E Toledano Furman, J You, M Ferrari, F Salvatore, E Tasciotti
Recent advances in the field of nanomedicine have demonstrated that biomimicry can further improve targeting properties of current nanotechnologies while simultaneously enable carriers with a biological identity to better interact with the biological environment. Immune cells for example employ membrane proteins to target inflamed vasculature, locally increase vascular permeability, and extravasate across inflamed endothelium. Inspired by the physiology of immune cells, we recently developed a procedure to transfer leukocyte membranes onto nanoporous silicon particles (NPS), yielding Leukolike Vectors (LLV)...
October 5, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27703032/superresolution-imaging-of-the-cytoplasmic-phosphatase-ptpn22-links-integrin-mediated-t-cell-adhesion-with-autoimmunity
#13
Garth L Burn, Georgina H Cornish, Katarzyna Potrzebowska, Malin Samuelsson, Juliette Griffié, Sophie Minoughan, Mark Yates, George Ashdown, Nicolas Pernodet, Vicky L Morrison, Cristina Sanchez-Blanco, Harriet Purvis, Fiona Clarke, Rebecca J Brownlie, Timothy J Vyse, Rose Zamoyska, Dylan M Owen, Lena M Svensson, Andrew P Cope
Integrins are heterodimeric transmembrane proteins that play a fundamental role in the migration of leukocytes to sites of infection or injury. We found that protein tyrosine phosphatase nonreceptor type 22 (PTPN22) inhibits signaling by the integrin lymphocyte function-associated antigen-1 (LFA-1) in effector T cells. PTPN22 colocalized with its substrates at the leading edge of cells migrating on surfaces coated with the LFA-1 ligand intercellular adhesion molecule-1 (ICAM-1). Knockout or knockdown of PTPN22 or expression of the autoimmune disease-associated PTPN22-R620W variant resulted in the enhanced phosphorylation of signaling molecules downstream of integrins...
October 4, 2016: Science Signaling
https://www.readbyqxmd.com/read/27697866/shp-1-acts-as-a-key-regulator-of-alloresponses-by-modulating-lfa-1-mediated-adhesion-in-primary-murine-t-cells
#14
Martin G Sauer, Jessica Herbst, Ulf Diekmann, Christopher E Rudd, Christian Kardinal
The clinical potential of transplantation is often reduced by T cell-mediated alloresponses that cause graft rejection or graft versus host disease. Integrin-mediated adhesion between alloreactive T cells and antigen-presenting cells is essential for allorejection. The identity of the signaling events needed to the activation of integrins such as LFA-1 is poorly understood. Here, we identify a novel role of the protein tyrosine phosphatase SHP-1 in the regulation of murine LFA-1-mediated adhesion in an allograft setting...
October 3, 2016: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/27690452/quantitative-protein-sulfenic-acid-analysis-identifies-platelet-releasate-induced-activation-of-integrin-%C3%AE-2-on-monocytes-via-nadph-oxidase
#15
Ru Li, Cordula Klockenbusch, Liwen Lin, Honghui Jiang, Shujun Lin, Juergen Kast
Physiological stimuli such as thrombin, or pathological stimuli such as lysophosphatidic acid (LPA), activate platelets. The activated platelets bind to monocytes through P-selectin-PSGL-1 interactions, but also release the contents of their granules, commonly called "platelet releasate". It is known that monocytes in contact with platelet releasate produce reactive oxygen species (ROS). Reversible cysteine oxidation by ROS is considered to be a potential regulator of protein function. In a previous study, we used THP-1 monocytic cells exposed to LPA- or thrombin-induced platelet releasate and a modified biotin switch assay to unravel the biological processes that are influenced by reversible cysteine oxidation...
October 3, 2016: Journal of Proteome Research
https://www.readbyqxmd.com/read/27623446/cell-contact-dependent-activation-of-cd4-t-cells-by-adhesion-molecules-on-synovial-fibroblasts
#16
Masato Mori, Motomu Hashimoto, Takashi Matsuo, Takao Fujii, Moritoshi Furu, Hiromu Ito, Hiroyuki Yoshitomi, Jun Hirose, Yoshinaga Ito, Shuji Akizuki, Ran Nakashima, Yoshitaka Imura, Naoichiro Yukawa, Hajime Yoshifuji, Koichiro Ohmura, Tsuneyo Mimori
OBJECTIVE: To determine how cell-cell contact with synovial fibroblasts (SF) influence on the proliferation and cytokine production of CD4(+ )T cells. METHODS: Naïve CD4(+ )T cells were cultured with SF from rheumatoid arthritis patients, stimulated by anti-CD3/28 antibody, and CD4(+ )T cell proliferation and IFN-γ/IL-17 production were analyzed. To study the role of adhesion molecules, cell contact was blocked by transwell plate or anti-intracellular adhesion molecule-1 (ICAM-1)/vascular cell adhesion molecule-1(VCAM-1) antibody...
September 13, 2016: Modern Rheumatology
https://www.readbyqxmd.com/read/27621421/correction-deletion-of-slam-locus-in-mice-reveals-inhibitory-role-of-slam-family-in-nk-cell-responses-regulated-by-cytokines-and-lfa-1
#17
Huaijian Guo, Stacey A Cranert, Yan Lu, Ming-Chao Zhong, Shaohua Zhang, Jun Chen, Rui Li, Sarah E Mahl, Ning Wu, Dominique Davidson, Stephen N Waggoner, André Veillette
No abstract text is available yet for this article.
September 19, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27613223/downstream-effect-profiles-discern-different-mechanisms-of-integrin-%C3%AE-l%C3%AE-2-inhibition
#18
Riccardo V Mancuso, Karl Welzenbach, Peter Steinberger, Stephan Krähenbühl, Gabriele Weitz-Schmidt
The integrin leucocyte function-associated antigen-1 (αLβ2, LFA-1) plays crucial roles in T cell adhesion, migration and immunological synapse (IS) formation. Consequently, αLβ2 is an important therapeutic target in autoimmunity. Three major classes of αLβ2 inhibitors with distinct modes of action have been described to date: Monoclonal antibodies (mAbs), small molecule α/β I allosteric and small molecule α I allosteric inhibitors. The objective of this study was to systematically compare these three modes of αLβ2 inhibition for their αLβ2 inhibitory as well as their potential agonist-like effects...
November 1, 2016: Biochemical Pharmacology
https://www.readbyqxmd.com/read/27573813/deletion-of-slam-locus-in-mice-reveals-inhibitory-role-of-slam-family-in-nk-cell-responses-regulated-by-cytokines-and-lfa-1
#19
Huaijian Guo, Stacey A Cranert, Yan Lu, Ming-Chao Zhong, Shaohua Zhang, Jun Chen, Rui Li, Sarah E Mahl, Ning Wu, Dominique Davidson, Stephen N Waggoner, André Veillette
Signaling lymphocytic activation molecule (SLAM) family receptors (SFRs) can mediate either activating or inhibitory effects during natural killer cell (NK cell) activation. In this study, we addressed the global role, regulation, and mechanism of action of the SLAM family in NK cells by analyzing a mouse lacking the entire ∼400-kilobase Slam locus, which encodes all six SFRs and CD48, the ligand of SFR 2B4. This mouse displayed enhanced NK cell activation responses toward hematopoietic target cells. Analyses of mice lacking individual SFRs showed that the inhibitory function of the Slam locus was due solely to 2B4 and was not influenced positively or negatively by other SFRs...
September 19, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27558417/lfa-1-engagement-triggers-t-cell-polarization-at-the-hiv-1-virological-synapse
#20
Shimona Starling, Clare Jolly
: HIV-1 efficiently disseminates by cell-cell spread at intercellular contacts called virological synapses (VS), where the virus preferentially assembles and buds. Cell-cell contact triggers active polarization of organelles and viral proteins within infected cells to the contact site to support efficient VS formation and HIV-1 spread; critically, however, which cell surface protein triggers contact-induced polarization at the VS remains unclear. Additionally, the mechanism by which the HIV-1 envelope glycoprotein (Env) is recruited to the VS remains ill defined...
November 1, 2016: Journal of Virology
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