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Lymphocyte exhaustion

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...
October 13, 2016: Current Opinion in Immunology
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
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
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
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
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
Shin Foong Ngiow, Arabella Young, Stephen J Blake, Geoffrey R Hill, Hideo Yagita, Michele Wl 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 PD1hi 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 PD1hi 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...
September 9, 2016: Cancer Research
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
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
Smriti Sharma, Richard E Davis, Shweta Srivastva, Susanne Nylén, Shyam Sundar, Mary E Wilson
BACKGROUND:  Visceral leishmaniasis (VL) is a potentially fatal parasitic disease associated with fever, cachexia and impaired protective T-cell responses against the parasite. METHODS:  Peripheral blood leukocytes from 105 subjects with VL and healthy control subjects from the endemic region of Muzaffarpur, Bihar, India, were compared using flow cytometry and reverse-transcriptase quantitative polymerase chain reaction. Findings were correlated with clinical data...
September 6, 2016: Journal of Infectious Diseases
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No abstract text is available yet for this article.
November 2016: Occupational and Environmental Medicine
David J Birnbaum, Pascal Finetti, Alexia Lopresti, Marine Gilabert, Flora Poizat, Olivier Turrini, Jean-Luc Raoul, Jean-Robert Delpero, Vincent Moutardier, Daniel Birnbaum, Emilie Mamessier, François Bertucci
Pancreatic cancer is one of the most aggressive human cancers. PD1/PDL1-inhibitors recently showed promising results in different cancers with correlation between PDL1 tumor expression and responses. Expression of programmed cell death receptor ligand 1 (PDL1) has been scarcely studied in pancreatic cancer. In this retrospective study, we analyzed PDL1 mRNA expression in 453 clinical pancreatic cancer samples profiled using DNA microarrays and RNASeq. Compared to normal pancreatic samples, PDL1 expression was upregulated in 19% of cancer samples...
August 29, 2016: Oncotarget
Eoin F McKinney, Kenneth G C Smith
During acute viral infection CD8 T cells rapidly expand before contracting down to a persistent memory population that confers long-lasting immunity. However when the antigen persists, such as during chronic viral infection, a dysfunctional process termed 'exhaustion' limits the antiviral response, facilitating ongoing viraemia and poor clinical outcome. CD8 T cell exhaustion was originally identified in lymphocytic choriomeningitis virus (LCMV) infection of mice however new evidence has shown that exhaustion is associated with the control of a wide range of human chronic inflammatory states including chronic viral infection, autoimmunity and cancer...
August 31, 2016: Immunology and Cell Biology
Xie Jinhua, Wang Ji, Cheng Shouliang, Zheng Liangfeng, Ji Feiyue, Yang Lin, Zhang Yan, Ji Haoming
Inhibition of immune checkpoint proteins (checkpoints) has become a promising anti-esophageal cancer strategy. We here tested expressions of immune checkpoints in human esophageal cancers. Our results showed the expressions of many immune checkpoints, including CD28, CD27, CD137L, programmed death 1 (PD-1), T cell immunoglobulin mucin-3 (TIM-3), T cell Ig and ITIM domain (TIGIT), CD160, cytotoxic T lymphocyte antigen 4 (CTLA-4), CD200, CD137 and CD158, were dysregulated in peripheral T cells of esophageal cancer patients...
August 25, 2016: Oncotarget
Jean-Christophe Beltra, Sara Bourbonnais, Nathalie Bédard, Tania Charpentier, Moana Boulangé, Eva Michaud, Ines Boufaied, Julie Bruneau, Naglaa H Shoukry, Alain Lamarre, Hélène Decaluwe
Exhaustion of CD8(+) T cells severely impedes the adaptive immune response to chronic viral infections. Despite major advances in our understanding of the molecular regulation of exhaustion, the cytokines that directly control this process during chronicity remain unknown. We demonstrate a direct impact of IL-2 and IL-15, two common gamma-chain-dependent cytokines, on CD8(+) T-cell exhaustion. Common to both cytokine receptors, the IL-2 receptor β (IL2Rβ) chain is selectively maintained on CD8(+) T cells during chronic lymphocytic choriomeningitis virus and hepatitis C virus infections...
September 13, 2016: Proceedings of the National Academy of Sciences of the United States of America
Horlad Hasita, Chaoya Ma, Hiromu Yano, Cheng Pan, Koji Ohnishi, Yukio Fujiwara, Shinya Endo, Yoshitaka Kikukawa, Yutaka Okuno, Masao Matsuoka, Motohiro Takeya, Yoshihiro Komohara
Immune escape and tolerance in the tumor microenvironment are closely involved in tumor progression, and are caused by T-cell exhaustion and mediated by the inhibitory signaling of immune checkpoint molecules including programmed death-1 (PD-1), cytotoxic T-lymphocyte associated protein 4, and T-cell immunoglobulin and mucin domain-containing molecule-3. In the present study, we investigated expression of the PD-1 ligand 1 (PD-L1) in a lymphoma microenvironment using paraffin embedded tissue samples, and subsequently studied the detailed mechanism of up-regulation of PD-L1 on macrophages using cultured human macrophages and lymphoma cell lines...
August 26, 2016: Cancer Science
Tatsunori Goto, Tetsuya Nishida, Erina Takagi, Kotaro Miyao, Daisuke Koyama, Reona Sakemura, Ryo Hanajiri, Keisuke Watanabe, Nobuhiko Imahashi, Seitaro Terakura, Makoto Murata, Hitoshi Kiyoi
Programmed death-ligand 1 (PD-L1) binds to programmed death-1 (PD-1) on activated T cells and contributes to T-cell exhaustion. PD-L1 expressed on antigen-presenting cells (APCs) could be thought to inhibit the induction of Ag-specific cytotoxic T lymphocytes (CTLs) by transducing negative signal into T cells; however, the roles of PD-L1 on APCs have not yet been well examined. Therefore, we evaluated the roles of PD-L1 on APCs in the induction of Ag-specific CTLs. CD3 T cells isolated from cytomegalovirus (CMV)-seropositive healthy donors were stimulated with mature dendritic cells pulsed with CMV pp65-derived HLA-restricted peptides in the presence of anti-PD-L1 blocking antibody...
October 2016: Journal of Immunotherapy
Adil I Daud, Kimberly Loo, Mariela L Pauli, Robert Sanchez-Rodriguez, Priscila Munoz Sandoval, Keyon Taravati, Katy Tsai, Adi Nosrati, Lorenzo Nardo, Michael D Alvarado, Alain P Algazi, Miguel H Pampaloni, Iryna V Lobach, Jimmy Hwang, Robert H Pierce, Iris K Gratz, Matthew F Krummel, Michael D Rosenblum
BACKGROUND: Immune checkpoint blockade is revolutionizing therapy for advanced cancer, but many patients do not respond to treatment. The identification of robust biomarkers that predict clinical response to specific checkpoint inhibitors is critical in order to stratify patients and to rationally select combinations in the context of an expanding array of therapeutic options. METHODS: We performed multiparameter flow cytometry on freshly isolated metastatic melanoma samples from 2 cohorts of 20 patients each prior to treatment and correlated the subsequent clinical response with the tumor immune phenotype...
September 1, 2016: Journal of Clinical Investigation
Se Jin Im, Masao Hashimoto, Michael Y Gerner, Junghwa Lee, Haydn T Kissick, Matheus C Burger, Qiang Shan, J Scott Hale, Judong Lee, Tahseen H Nasti, Arlene H Sharpe, Gordon J Freeman, Ronald N Germain, Helder I Nakaya, Hai-Hui Xue, Rafi Ahmed
Chronic viral infections are characterized by a state of CD8(+) T cell dysfunction that is associated with expression of the programmed cell death 1 (PD-1) inhibitory receptor(1-4). A better understanding of the mechanisms that regulate CD8(+) T cell responses during chronic infection is required to improve immunotherapies that restore function in exhausted CD8(+) T cells. Here we identify the population of virus-specific CD8(+) T cells that proliferate after blockade of the PD-1 inhibitory pathway in mice chronically infected with lymphocytic choriomeningitis virus (LCMV)...
August 2, 2016: Nature
Ran He, Shiyue Hou, Cheng Liu, Anli Zhang, Qiang Bai, Miao Han, Yu Yang, Gang Wei, Ting Shen, Xinxin Yang, Lifan Xu, Xiangyu Chen, Yaxing Hao, Pengcheng Wang, Chuhong Zhu, Juanjuan Ou, Houjie Liang, Ting Ni, Xiaoyan Zhang, Xinyuan Zhou, Kai Deng, Yaokai Chen, Yadong Luo, Jianqing Xu, Hai Qi, Yuzhang Wu, Lilin Ye
During chronic viral infection, virus-specific CD8(+) T cells become exhausted, exhibit poor effector function and lose memory potential. However, exhausted CD8(+) T cells can still contain viral replication in chronic infections, although the mechanism of this containment is largely unknown. Here we show that a subset of exhausted CD8(+) T cells expressing the chemokine receptor CXCR5 has a critical role in the control of viral replication in mice that were chronically infected with lymphocytic choriomeningitis virus (LCMV)...
August 2, 2016: Nature
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