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Lymphocyte exhaustion

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https://www.readbyqxmd.com/read/27903862/improved-cancer-immunotherapy-by-a-cd25-mimobody-conferring-selectivity-to-human-interleukin-2
#1
Natalia Arenas-Ramirez, Chao Zou, Simone Popp, Daniel Zingg, Barbara Brannetti, Emmanuelle Wirth, Thomas Calzascia, Jiri Kovarik, Lukas Sommer, Gerhard Zenke, Janine Woytschak, Catherine H Regnier, Andreas Katopodis, Onur Boyman
Interleukin-2 (IL-2) immunotherapy is an attractive approach in treating advanced cancer. However, by binding to its IL-2 receptor α (CD25) subunit, IL-2 exerts unwanted effects, including stimulation of immunosuppressive regulatory T cells (Tregs) and contribution to vascular leak syndrome. We used a rational approach to develop a monoclonal antibody to human IL-2, termed NARA1, which acts as a high-affinity CD25 mimic, thereby minimizing association of IL-2 with CD25. The structure of the IL-2-NARA1 complex revealed that NARA1 occupies the CD25 epitope of IL-2 and precisely overlaps with CD25...
November 30, 2016: Science Translational Medicine
https://www.readbyqxmd.com/read/27902325/targeting-naturally-occurring-epitope-variants-of-hepatitis-c-virus-with-high-affinity-t-cell-receptors
#2
Huajun Zhang, Jianbing Zhang, Lei Chen, Zhiming Weng, Ye Tian, Haifeng Zhao, Youjia Li, Lin Chen, Zhaoduan Liang, Hongjun Zheng, Wenzhuo Zhao, Shi Zhong, Yi Li
Hepatitis C virus (HCV) readily establishes chronic infection, which is characterized by failure of virus-specific CD8+ T cells. HCV uses epitope mutation and T-cell exhaustion to escape from the host immune response. Previously, we engineered high-affinity T-cell receptors (HATs) targeting HIV escape mutants. In this study, the affinity of a T-cell receptor specific for the human leukocyte antigen (HLA)-A2-restricted HCV immunodominant epitope NS3 1406-1415 (KLVALGINAV) was improved from a KD of 6.6 µM to 40 pM...
November 11, 2016: Journal of General Virology
https://www.readbyqxmd.com/read/27895178/conserved-region-c-functions-to-regulate-pd-1-expression-and-subsequent-cd8-t-cell-memory
#3
Alexander P R Bally, Yan Tang, Joshua T Lee, Benjamin G Barwick, Ryan Martinez, Brian D Evavold, Jeremy M Boss
Expression of programmed death 1 (PD-1) on CD8 T cells promotes T cell exhaustion during chronic Ag exposure. During acute infections, PD-1 is transiently expressed and has the potential to modulate CD8 T cell memory formation. Conserved region C (CR-C), a promoter proximal cis-regulatory element that is critical to PD-1 expression in vitro, responds to NFATc1, FoxO1, and/or NF-κB signaling pathways. Here, a CR-C knockout mouse was established to determine its role on PD-1 expression and the corresponding effects on T cell function in vivo...
November 28, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27853635/tumor-infiltrating-tim-3-t-cells-proliferate-avidly-except-when-pd-1-is-co-expressed-evidence-for-intracellular-cross-talk
#4
Jing Li, Gulidanna Shayan, Lyndsay Avery, Hyun-Bae Jie, Neil Gildener-Leapman, Nicole Schmitt, Bin Feng Lu, Lawrence P Kane, Robert L Ferris
Programmed Death 1 (PD-1) and T cell Ig and mucin domain-3 protein (Tim-3) are immune checkpoint receptors highly expressed on tumor infiltrating T lymphocytes (TIL). PD-1 inhibits T cell activation and type-1 T cell responses, while Tim-3 is proposed to mark more extensively exhausted cells, although the mechanisms underlying Tim-3 function are not clear. Trials of anti-PD-1 therapy have identified a large subset of non-responder patients, likely due to expression of alternative checkpoint molecules like Tim-3...
2016: Oncoimmunology
https://www.readbyqxmd.com/read/27835902/squamous-cell-carcinomas-escape-immune-surveillance-via-inducing-chronic-activation-and-exhaustion-of-cd8-t-cells-co-expressing-pd-1-and-lag-3-inhibitory-receptors
#5
Ameet K Mishra, Tanya Kadoishi, Xiaoguang Wang, Emily Driver, Zhangguo Chen, Xiao-Jing Wang, Jing H Wang
Squamous cell carcinoma (SCC) is the second commonest type of skin cancer. Moreover, about 90% of head and neck cancers are SCCs. SCCs develop at a significantly higher rate under chronic immunosuppressive conditions, implicating a role of immune surveillance in controlling SCCs. It remains largely unknown how SCCs evade immune recognition. Here, we established a mouse model by injecting tumor cells derived from primary SCCs harboring KrasG12D mutation and Smad4 deletion into wild-type (wt) or CD8-/- recipients...
November 9, 2016: Oncotarget
https://www.readbyqxmd.com/read/27826124/-off-the-shelf-immunotherapy-with-ipsc-derived-rejuvenated-cytotoxic-t-lymphocytes
#6
Miki Ando, Hiromitsu Nakauchi
Adoptive T cell therapy to target and kill tumor cells shows promise and induces durable remissions in selected malignancies. However, for most cancers, clinical utility is limited. Cytotoxic T lymphocytes (CTLs) continuously exposed to viral or tumor antigens, with long-term expansion, may become unable to proliferate ("exhausted"). To exploit fully rejuvenated induced pluripotent stem cell (iPSC)-derived antigen-specific CTLs is a potentially powerful approach. We review recent progress in engineering iPSC-derived T cells and prospects for clinical translation...
November 5, 2016: Experimental Hematology
https://www.readbyqxmd.com/read/27810927/scramblase-tmem16f-terminates-t-cell-receptor-signaling-to-restrict-t-cell-exhaustion
#7
Yu Hu, Ji Hyung Kim, Kangmin He, Qi Wan, Jessica Kim, Melanie Flach, Tom Kirchhausen, Andrea Vortkamp, Florian Winau
In chronic infection, T cells become hyporesponsive to antigenic stimulation to prevent immunopathology. Here, we show that TMEM16F is required to curb excessive T cell responses in chronic infection with virus. TMEM16F-deficient T cells are hyperactivated during the early phase of infection, exhibiting increased proliferation and cytokine production. Interestingly, this overactivation ultimately leads to severe T cell exhaustion and the inability of the host to control viral burden. Mechanistically, we identify TMEM16F as the dominant lipid scramblase in T lymphocytes that transports phospholipids across membranes...
November 14, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27809306/cd169-macrophages-regulate-pd-l1-expression-via-type-i-interferon-and-thereby-prevent-severe-immunopathology-after-lcmv-infection
#8
Namir Shaabani, Vikas Duhan, Vishal Khairnar, Asmae Gassa, Rita Ferrer-Tur, Dieter Häussinger, Mike Recher, Gennadiy Zelinskyy, Jia Liu, Ulf Dittmer, Mirko Trilling, Stefanie Scheu, Cornelia Hardt, Philipp A Lang, Nadine Honke, Karl S Lang
Upon infection with persistence-prone virus, type I interferon (IFN-I) mediates antiviral activity and also upregulates the expression of programmed death ligand 1 (PD-L1), and this upregulation can lead to CD8(+) T-cell exhaustion. How these very diverse functions are regulated remains unknown. This study, using the lymphocytic choriomeningitis virus, showed that a subset of CD169(+) macrophages in murine spleen and lymph nodes produced high amounts of IFN-I upon infection. Absence of CD169(+) macrophages led to insufficient production of IFN-I, lower antiviral activity and persistence of virus...
November 3, 2016: Cell Death & Disease
https://www.readbyqxmd.com/read/27801952/human-t-lymphocytes-bioactivate-heterocyclic-aromatic-amines-by-forming-dna-adducts
#9
Medjda Bellamri, Ludovic Le Hegarat, Laurent Vernhet, Georges Baffet, Robert J Turesky, Sophie Langouët
Heterocyclic aromatic amines (HAA) are formed in cooked meat, poultry and fish but also arise in tobacco smoke and exhaust gases. HAA are potential human carcinogens, which require metabolic activation to exert their genotoxicity. Human tissues can bioactivate HAA to produce reactive intermediates that bind to DNA. HAA DNA adduct formation occurs in human hepatocytes; however, the potential of HAA to form DNA adducts has not been investigated in human T lymphocytes. In this study, we investigated the ability of human T lymphocytes activated with PMA/Ionomycin or CD3/CD28 to express functional CYP1 activity and bioactivate three major HAA: 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), and 2-amino-9H-pyrido[2,3-b]indole (AαC) to form DNA adducts...
December 2016: Environmental and Molecular Mutagenesis
https://www.readbyqxmd.com/read/27799548/ptpn22-contributes-to-exhaustion-of-t-lymphocytes-during-chronic-viral-infection
#10
Christian J Maine, John R Teijaro, Kristi Marquardt, Linda A Sherman
The protein encoded by the autoimmune-associated protein tyrosine phosphatase nonreceptor type 22 gene, PTPN22, has wide-ranging effects in immune cells including suppression of T-cell receptor signaling and promoting efficient production of type I interferons (IFN-I) by myeloid cells. Here we show that mice deficient in PTPN22 resist chronic viral infection with lymphocytic choriomeningitis virus clone 13 (LCMV cl13). The numbers and function of viral-specific CD4 T lymphocytes is greatly enhanced, whereas expression of the IFNβ-induced IL-2 repressor, cAMP-responsive element modulator (CREM) is reduced...
October 31, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27770382/immune-checkpoint-inhibitors-for-cancer-treatment
#11
REVIEW
Junsik Park, Minsuk Kwon, Eui-Cheol Shin
During immune responses antigen-specific T cells are regulated by several mechanisms, including through inhibitory receptors and regulatory T cells, to avoid excessive or persistent immune responses. These regulatory mechanisms, which are called 'immune checkpoints', suppress T cell responses, particularly in patients with chronic viral infections and cancer where viral antigens or tumor antigens persist for a long time and contribute to T cell exhaustion. Among these regulatory mechanisms, cytotoxic T lymphocyte associated protein-4 (CTLA-4) and programmed cell death 1 (PD-1) are the most well-known receptors and both have been targeted for drug development...
November 2016: Archives of Pharmacal Research
https://www.readbyqxmd.com/read/27744240/t-cell-exhaustion-and-immune-mediated-disease-the-potential-for-therapeutic-exhaustion
#12
REVIEW
Eoin F McKinney, Kenneth Gc Smith
T cell exhaustion represents a continuous spectrum of cellular dysfunction induced during chronic viral infection, facilitating viral persistence and associating with poor clinical outcome. Modulation of T cell exhaustion can restore function in exhausted CD8 T cells, promoting viral clearance. Exhaustion has also been implicated as playing an important role in anti-tumour responses, whereby exhausted tumour-infiltrating lymphocytes fail to control tumour progression. More recently exhaustion has been linked to long-term clinical outcome in multiple autoimmune diseases but, in contrast to cancer or infection, it is associated with a favourable clinical outcome characterised by fewer relapses...
December 2016: Current Opinion in Immunology
https://www.readbyqxmd.com/read/27743606/hepatic-expansion-of-virus-specific-cd8-btla-t-cells-with-regulatory-properties-in-chronic-hepatitis-b-virus-infection
#13
Huaizhou Wang, Beiying Wu, Lei Li, Liang Hu, Jiafei Lin, Cen Jiang, Gang Cai, Qian Shen
Similar to programmed death-1 (PD-1), B and T lymphocyte attenuator (BTLA) is a co-inhibitory molecule of the CD28 family. PD-1 is involved in T cell exhaustion during chronic viral infection. However, the role of BTLA in virus-specific T cells is poorly defined. Here we investigated the expression and function of BTLA in T cells from patients with chronic hepatitis B virus (HBV) infection. The phenotype of peripheral and intrahepatic HBV-specific T cells from 43 patients with chronic HBV infection was assessed by flow cytometry...
October 6, 2016: Cellular Immunology
https://www.readbyqxmd.com/read/27725355/immune-exhaustion-during-chronic-infections-in-cattle
#14
Satoru Konnai, Shiro Murata, Kazuhiko Ohashi
Recently, dysfunction of antigen-specific T cells is well documented as T-cell exhaustion and has been defined by the loss of effector functions during chronic infections and cancer in human. The exhausted T cells are characterized phenotypically by the surface expression of immunoinhibitory receptors, such as programmed death 1 (PD-1), lymphocyte activation gene 3 (LAG-3), T-cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) and cytotoxic T-lymphocyte antigen 4 (CTLA-4). However, there is still a fundamental lack of knowledge about the immunoinhibitory receptors in the fields of veterinary medicine...
October 8, 2016: Journal of Veterinary Medical Science
https://www.readbyqxmd.com/read/27662664/pd-1-mediates-functional-exhaustion-of-activated-nk-cells-in-patients-with-kaposi-sarcoma
#15
Asma Beldi-Ferchiou, Marion Lambert, Stéphanie Dogniaux, Frédéric Vély, Eric Vivier, Daniel Olive, Stéphanie Dupuy, Frank Levasseur, David Zucman, Céleste Lebbé, Damien Sène, Claire Hivroz, Sophie Caillat-Zucman
Programmed Death-1 (PD-1), an inhibitory receptor expressed by activated lymphocytes, is involved in regulating T- and B-cell responses. PD-1 and its ligands are exploited by a variety of cancers to facilitate tumor escape through PD-1-mediated functional exhaustion of effector T cells. Here, we report that PD-1 is upregulated on Natural Killer (NK) cells from patients with Kaposi sarcoma (KS). PD-1 was expressed in a sub-population of activated, mature CD56dimCD16pos NK cells with otherwise normal expression of NK surface receptors...
September 20, 2016: Oncotarget
https://www.readbyqxmd.com/read/27659428/prevention-of-allograft-rejection-in-heart-transplantation-through-concurrent-gene-silencing-of-tlr-and-kinase-signaling-pathways
#16
Hongmei Wang, Xusheng Zhang, Xiufen Zheng, Zhu Lan, Jun Shi, Jifu Jiang, Terry Zwiep, Qing Li, Douglas Quan, Zhu-Xu Zhang, Weiping Min
Toll-like receptors (TLRs) act as initiators and conductors responsible for both innate and adaptive immune responses in organ transplantation. The mammalian target of rapamycin (mTOR) is one of the most critical signaling kinases that affects broad aspects of cellular functions including metabolism, growth, and survival. Recipients (BALB/c) were treated with MyD88, TRIF and mTOR siRNA vectors, 3 and 7 days prior to heart transplantation and 7, 14 and 21 days after transplantation. After siRNA treatment, recipients received a fully MHC-mismatched C57BL/6 heart...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27638944/t-cell-immunoglobulin-and-mucin-domain-containing-molecule-3-tim-3-signalling-blockade-improves-cell-mediated-immunity-against-malaria
#17
Nan Hou, Yang Zou, Xianyu Piao, Shuai Liu, Lei Wang, Shanshan Li, Qijun Chen
Cell-mediated immune responses play important roles in immune protection against Plasmodium infection. However, impaired immunity, such as lymphocyte exhaustion, is a common phenomenon in malaria. T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) is an important regulatory molecule in cell-mediated immunity and has been implicated in malaria. In this study, it was found that the expression of Tim-3 expression on key populations of lymphocytes was significantly increased in both Plasmodium falciparum-infected patients and Plasmodium berghei ANKA (PbANKA)-infected C57BL/6 mice...
September 16, 2016: Journal of Infectious Diseases
https://www.readbyqxmd.com/read/27634762/agonistic-cd40-mab-driven-il12-reverses-resistance-to-anti-pd1-in-a-t-cell-rich-tumor
#18
Shin Foong Ngiow, Arabella Young, Stephen J Blake, Geoffrey R Hill, Hideo Yagita, Michele W L Teng, Alan J Korman, Mark J Smyth
The durability and efficacy of anti-human PD1 monoclonal antibodies (PD1 mAb) vary across different malignancies. Although an absence of tumor-infiltrating cytotoxic T lymphocytes has been identified as a cause for resistance to PD1 mAb, the presence of intratumor exhausted PD1(hi) T cells also contributes to insensitivity to this immune checkpoint therapy. In this study, we used mouse tumor models of PD1 mAb resistance that harbored PD1(hi) T cells and flow cytometry analysis of tumor-infiltrating leukocytes immediately post-therapy as a screening platform to identify agents that could resensitize T cells to PD1 blockade...
November 1, 2016: Cancer Research
https://www.readbyqxmd.com/read/27622060/biphasic-function-of-tlr3-adjuvant-on-tumor-and-spleen-dendritic-cells-promotes-tumor-t-cell-infiltration-and-regression-in-a-vaccine-therapy
#19
Masahiro Azuma, Yohei Takeda, Hiroko Nakajima, Haruo Sugiyama, Takashi Ebihara, Hiroyuki Oshiumi, Misako Matsumoto, Tsukasa Seya
Successful cancer immunotherapy necessitates T cell proliferation and infiltration into tumor without exhaustion, a process closely links optimal maturation of dendritic cells (DC), and adjuvant promotes this process as an essential prerequisite. Poly(I:C) has contributed to adjuvant immunotherapy that evokes an antitumor response through the Toll-loke receptor 3 (TLR3)/TICAM-1 pathway in DC. However, the mechanism whereby Poly(I:C) acts on DC for T cell proliferation and migration remains undetermined. Subcutaneous injection of Poly(I:C) regressed implant tumors (WT1-C1498 or OVA-EG7) in C57BL/6 mice, which coincided with tumor-infiltration of CD8(+) T cells...
August 2016: Oncoimmunology
https://www.readbyqxmd.com/read/27605882/specific-cd8-t-cell-response-immunotherapy-for-hepatocellular-carcinoma-and-viral-hepatitis
#20
REVIEW
Elia Moreno-Cubero, Juan-Ramón Larrubia
Hepatocellular carcinoma (HCC), chronic hepatitis B (CHB) and chronic hepatitis C (CHC) are characterized by exhaustion of the specific CD8(+) T cell response. This process involves enhancement of negative co-stimulatory molecules, such as programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte antigen-4 (CTLA-4), 2B4, Tim-3, CD160 and LAG-3, which is linked to intrahepatic overexpression of some of the cognate ligands, such as PD-L1, on antigen presenting cells and thereby favouring a tolerogenic environment...
July 28, 2016: World Journal of Gastroenterology: WJG
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