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Lymphocyte exhaustion

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https://www.readbyqxmd.com/read/29770136/cd3%C3%AE%C2%B5-expression-defines-functionally-distinct-subsets-of-v%C3%AE-1-t-cells-in-patients-with-human-immunodeficiency-virus-infection
#1
Pádraic J Dunne, Christina O Maher, Michael Freeley, Katie Dunne, Andreea Petrasca, Judy Orikiiriza, Margaret R Dunne, Derval Reidy, Siobhan O'Dea, Aisling Loy, Jim Woo, Aideen Long, Thomas R Rogers, Fiona Mulcahy, Derek G Doherty
Human γδ T cells expressing the Vδ1 T cell receptor (TCR) recognize self and microbial antigens and stress-inducible molecules in a major histocompatibility complex-unrestricted manner and are an important source of innate interleukin (IL)-17. Vδ1 T cells are expanded in the circulation and intestines of patients with human immunodeficiency virus (HIV) infection. In this study, we show that patients with HIV have elevated frequencies, but not absolute numbers, of circulating Vδ1 T cells compared to control subjects...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29769011/evolving-strategies-for-the-treatment-of-t-cell-lymphoma-a-systematic-review-and-recent-patents
#2
Kamel Laribi, Mustapha Alani, Catherine Truong, Alix Baugier de Materre
OBJECTIVE: Mature T-cell lymphomas are a heterogeneous group of T-cell malignancies with a poor outcome. The discovery of new molecular biomarkers has led to the emergence of new drugs in recent years that target various signaling pathways. METHOD: We examined all pertinent published patents through 2015 that analyzed novel methods for the diagnosis and treatment of T cell lymphoma, as well as related published and unpublished studies. Selection criteria were established before data collection...
May 16, 2018: Recent Patents on Anti-cancer Drug Discovery
https://www.readbyqxmd.com/read/29768211/long-term-persistence-of-exhausted-cd8-t-cells-in-chronic-infection-is-regulated-by-microrna-155
#3
Erietta Stelekati, Zeyu Chen, Sasikanth Manne, Makoto Kurachi, Mohammed-Alkhatim Ali, Keith Lewy, Zhangying Cai, Kito Nzingha, Laura M McLane, Jennifer L Hope, Adam J Fike, Peter D Katsikis, E John Wherry
Persistent viral infections and tumors drive development of exhausted T (TEX ) cells. In these settings, TEX cells establish an important host-pathogen or host-tumor stalemate. However, TEX cells erode over time, leading to loss of pathogen or cancer containment. We identified microRNA (miR)-155 as a key regulator of sustained TEX cell responses during chronic lymphocytic choriomeningitis virus (LCMV) infection. Genetic deficiency of miR-155 ablated CD8 T cell responses during chronic infection. Conversely, enhanced miR-155 expression promoted expansion and long-term persistence of TEX cells...
May 15, 2018: Cell Reports
https://www.readbyqxmd.com/read/29751531/computational-analysis-of-the-interaction-energies-between-amino-acid-residues-of-the-measles-virus-hemagglutinin-and-its-receptors
#4
Fengqi Xu, Shigenori Tanaka, Hirofumi Watanabe, Yasuhiro Shimane, Misako Iwasawa, Kazue Ohishi, Tadashi Maruyama
Measles virus (MV) causes an acute and highly devastating contagious disease in humans. Employing the crystal structures of three human receptors, signaling lymphocyte-activation molecule (SLAM), CD46, and Nectin-4, in complex with the measles virus hemagglutinin (MVH), we elucidated computationally the details of binding energies between the amino acid residues of MVH and those of the receptors with an ab initio fragment molecular orbital (FMO) method. The calculated inter-fragment interaction energies (IFIEs) revealed a number of significantly interacting amino acid residues of MVH that played essential roles in binding to the receptors...
May 3, 2018: Viruses
https://www.readbyqxmd.com/read/29746555/human-herpes-virus-8-in-hiv-1-infected-individuals-receiving-cancer-chemotherapy-and-stem-cell-transplantation
#5
Louise E Hogan, Emily Hanhauser, Kristen S Hobbs, Christine D Palmer, Yvonne Robles, Stephanie Jost, Anne S LaCasce, Jeremy Abramson, Ayad Hamdan, Francisco M Marty, Daniel R Kuritzkes, Timothy J Henrich
BACKGROUND: Human Herpes Virus 8 (HHV8) can cause Kaposi's Sarcoma (KS) in immunosuppressed individuals. However, little is known about the association between chemotherapy or hematopoietic stem cell transplantation (HSCT), circulating HHV8 DNA levels, and clinical KS in HIV-1-infected individuals with various malignancies. Therefore, we examined the associations between various malignancies, systemic cancer chemotherapy, T cell phenotypes, and circulating HHV8 DNA in 29 HIV-1-infected participants with concomitant KS or other cancer diagnoses...
2018: PloS One
https://www.readbyqxmd.com/read/29744934/modelling-how-reversal-of-immune-exhaustion-elicits-cure-of-chronic-hepatitis-c-after-the-end-of-treatment-with-direct-acting-antiviral-agents
#6
Subhasish Baral, Rahul Roy, Narendra M Dixit
A fraction of chronic hepatitis C patients treated with direct-acting antivirals (DAAs) achieved sustained virological responses (SVR), or cure, despite having detectable viremia at the end of treatment (EOT). This observation, termed EOT+ /SVR, remains puzzling and precludes rational optimization of treatment durations. One hypothesis to explain EOT+ /SVR, the immunologic hypothesis, argues that the viral decline induced by DAAs during treatment reverses the exhaustion of cytotoxic T lymphocytes (CTLs), which then clear the infection after treatment...
May 9, 2018: Immunology and Cell Biology
https://www.readbyqxmd.com/read/29713085/determinants-of-response-and-resistance-to-cd19-chimeric-antigen-receptor-car-t-cell-therapy-of-chronic-lymphocytic-leukemia
#7
Joseph A Fraietta, Simon F Lacey, Elena J Orlando, Iulian Pruteanu-Malinici, Mercy Gohil, Stefan Lundh, Alina C Boesteanu, Yan Wang, Roddy S O'Connor, Wei-Ting Hwang, Edward Pequignot, David E Ambrose, Changfeng Zhang, Nicholas Wilcox, Felipe Bedoya, Corin Dorfmeier, Fang Chen, Lifeng Tian, Harit Parakandi, Minnal Gupta, Regina M Young, F Brad Johnson, Irina Kulikovskaya, Li Liu, Jun Xu, Sadik H Kassim, Megan M Davis, Bruce L Levine, Noelle V Frey, Donald L Siegel, Alexander C Huang, E John Wherry, Hans Bitter, Jennifer L Brogdon, David L Porter, Carl H June, J Joseph Melenhorst
Tolerance to self-antigens prevents the elimination of cancer by the immune system1,2 . We used synthetic chimeric antigen receptors (CARs) to overcome immunological tolerance and mediate tumor rejection in patients with chronic lymphocytic leukemia (CLL). Remission was induced in a subset of subjects, but most did not respond. Comprehensive assessment of patient-derived CAR T cells to identify mechanisms of therapeutic success and failure has not been explored. We performed genomic, phenotypic and functional evaluations to identify determinants of response...
April 30, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29712685/novel-effector-phenotype-of-tim-3-regulatory-t-cells-leads-to-enhanced-suppressive-function-in-head-and-neck-cancer-patients
#8
Zhuqing Liu, Elizabeth L McMichael, Gulidanna Shayan, Jing Li, Kevin Chen, Raghvendra M Srivastava, Lawrence P Kane, Binfeng Lu, Robert L Ferris
PURPOSE: Regulatory T (Treg) cells are important suppressive cells among tumor infiltrating lymphocytes (TIL). Treg express the well-known immune checkpoint receptor PD-1, which is reported to mark "exhausted" Treg with lower suppressive function. T cell immunoglobulin mucin (Tim)-3, a negative regulator of Th1 immunity, is expressed by a sizeable fraction of TIL Tregs, but the functional status of Tim-3+ Tregs remains unclear. EXPERIMENTAL DESIGN: CD4+CTLA-4+CD25high Treg were sorted from freshly excised head and neck squamous cell carcinoma (HNSCC) TIL based on Tim-3 expression...
April 30, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29706626/long-non-coding-rna-lnc-tim3-exacerbates-cd8-t-cell-exhaustion-via-binding-to-tim-3-and-inducing-nuclear-translocation-of-bat3-in-hcc
#9
Jie Ji, Yin Yin, Huanyu Ju, Xiaoliang Xu, Wei Liu, Qiang Fu, Jiaojiao Hu, Xudong Zhang, Beicheng Sun
Although one of the first comprehensive examinations of long non-coding RNA (lncRNA) expression was performed in human CD8 T lymphocytes, little is known about their roles in CD8 T cells functions during the progression of hepatocellular carcinoma (HCC). Here, we show that Lnc-Tim3 is upregulated and negatively correlates with IFN-γ and IL-2 production in tumor-infiltrating CD8 T cells of HCC patients. Lnc-Tim3 plays a pivotal role in stimulating CD8 T exhaustion and the survival of the exhausted CD8 T cells...
April 30, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29691251/nfatc1-promotes-anti-tumoral-effector-functions-and-memory-cd8-t-cell-differentiation-during-non-small-cell-lung-cancer-development
#10
Lisanne Heim, Juliane Friedrich, Marina Engelhardt, Denis I Trufa, Carol I Geppert, Ralf Joachim Rieker, Horia Sirbu, Susetta Finotto
Nuclear factor of activated T cells 1 (NFATc1) is a transcription factor activated by T cell receptor (TCR) and Ca2+-signaling that affects T cell activation and effector function. Upon tumor antigen challenge, TCR and calcium-release-activated channels are induced, promoting NFAT dephosphorylation and translocation into the nucleus. In this study, we report a progressive decrease of NFATc1 in lung tumor tissue and in tumor-infiltrating lymphocytes (TIL) of patients suffering from advanced stage non-small cell lung cancer (NSCLC)...
April 24, 2018: Cancer Research
https://www.readbyqxmd.com/read/29672594/type-i-interferon-signaling-attenuates-regulatory-t-cell-function-in-viral-infection-and-in-the-tumor-microenvironment
#11
Arunakumar Gangaplara, Craig Martens, Eric Dahlstrom, Amina Metidji, Ameya S Gokhale, Deborah D Glass, Maria Lopez-Ocasio, Rachel Baur, Kishore Kanakabandi, Stephen F Porcella, Ethan M Shevach
Regulatory T cells (Tregs) play a cardinal role in the immune system by suppressing detrimental autoimmune responses, but their role in acute, chronic infectious diseases and tumor microenvironment remains unclear. We recently demonstrated that IFN-α/β receptor (IFNAR) signaling promotes Treg function in autoimmunity. Here we dissected the functional role of IFNAR-signaling in Tregs using Treg-specific IFNAR deficient (IFNARfl/flxFoxp3YFP-Cre) mice in acute LCMV Armstrong, chronic Clone-13 viral infection, and in tumor models...
April 19, 2018: PLoS Pathogens
https://www.readbyqxmd.com/read/29666149/genetic-and-phenotypic-difference-in-cd8-t-cell-exhaustion-between-chronic-hepatitis-b-infection-and-hepatocellular-carcinoma
#12
Xiaochen Wang, Qifeng He, Haiyuan Shen, Xiao-Jie Lu, Beicheng Sun
BACKGROUND: Several recent studies published have suggested that T cell exhaustion exists both in chronic infection and cancer. However, to date, few studies have investigated their differences. Here we designed this study to explore the genetic and phenotypic difference in CD8+ T cell exhaustion between chronic hepatitis B (CHB) and hepatocellular carcinoma (HCC). METHODS: In this study, we assayed the phenotypes and functional states of CD8+ T cells separating from human CHB tissues and HCC tissues, and re-analyse the single-cell sequencing data (GSE98638) published previously...
April 17, 2018: Journal of Medical Genetics
https://www.readbyqxmd.com/read/29661225/lymphocyte-subset-expression-and-serum-concentrations-of-pd-1-pd-l1-in-sepsis-pilot-study
#13
Julie K Wilson, Yuan Zhao, Mervyn Singer, Jo Spencer, Manu Shankar-Hari
BACKGROUND: Sepsis remains a major cause of mortality in critical care, for which specific treatments are lacking. The dysregulated response to infection seen in sepsis includes features of lymphocyte dysfunction and exhaustion, suggesting that immune-stimulatory therapy may improve outcomes in certain patient groups. Monoclonal antibodies targeting checkpoint molecules, such as programmed-death 1 protein (PD-1) and its ligand PD-L1, have shown success in stimulating the immune response in patients with cancer, and are being considered for future sepsis trials...
April 17, 2018: Critical Care: the Official Journal of the Critical Care Forum
https://www.readbyqxmd.com/read/29656492/pd-1-blockade-cellular-vesicles-for-cancer-immunotherapy
#14
Xudong Zhang, Chao Wang, Jinqiang Wang, Quanyin Hu, Benjamin Langworthy, Yanqi Ye, Wujin Sun, Jing Lin, Tianfu Wang, Jason Fine, Hao Cheng, Gianpietro Dotti, Peng Huang, Zhen Gu
Cancer cells resist to the host immune antitumor response via multiple suppressive mechanisms, including the overexpression of PD-L1 that exhausts antigen-specific CD8+ T cells through PD-1 receptors. Checkpoint blockade antibodies against PD-1 or PD-L1 have shown unprecedented clinical responses. However, limited host response rate underlines the need to develop alternative engineering approaches. Here, engineered cellular nanovesicles (NVs) presenting PD-1 receptors on their membranes, which enhance antitumor responses by disrupting the PD-1/PD-L1 immune inhibitory axis, are reported...
April 14, 2018: Advanced Materials
https://www.readbyqxmd.com/read/29649617/reversal-of-t-cell-exhaustion-by-the-first-donor-lymphocyte-infusion-is-associated-with-the-persistently-effective-anti-leukemic-responses-in-patients-with-relapsed-aml-after-allo-hsct
#15
Long Liu, Ying-Jun Chang, Lan-Ping Xu, Xiao-Hui Zhang, Yu Wang, Kai-Yan Liu, Xiao-Jun Huang
Donor lymphocyte infusion is an effective approach to treat acute myeloid leukemia (AML) relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) that significantly improves the survival of relapsed patients. However, the mechanism of an effective anti-leukemic response following DLI in AML relapse remains elusive. Here, we investigated the role of T cell exhaustion in AML relapse after allo-HSCT in prospective cohorts of 41 patients with the first AML relapse and 41 non-relapsed AML controls after allo-HSCT and determined whether DLI exerts effective anti-leukemic effects by reversing T cell exhaustion in the relapsed cohorts by detecting the phenotypes and functions of T cells using flow cytometry...
April 9, 2018: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/29620933/dynamics-of-lymphocyte-reconstitution-after-hematopoietic-transplantation-during-chronic-lymphocytic-choriomeningitis-virus-infection
#16
Mitra Bhattacharyya, Pablo Penaloza-MacMaster
Bone marrow transplantation is a treatment for various cancers and genetic diseases, and the only case of a cured HIV infection involved the use of this clinical procedure, highlighting the potential use of this therapy for curing many chronic diseases. However, little is known about how chronic viral infection influences lymphocyte reconstitution after bone marrow transplantation. To address this, we infected mice with chronic lymphocytic choriomeningitis virus, and performed bone marrow transplantation to assess lymphocyte reconstitution...
May 2018: AIDS Research and Human Retroviruses
https://www.readbyqxmd.com/read/29619420/changes-in-natural-killer-cells-and-exhausted-memory-regulatory-t-cells-with-corticosteroid-therapy-in-acute-autoimmune-hepatitis
#17
Hannah C Jeffery, Manjit K Braitch, Chris Bagnall, James Hodson, Louisa E Jeffery, Rebecca E Wawman, Lin Lee Wong, Jane Birtwistle, Helen Bartlett, Ansgar W Lohse, Gideon M Hirschfield, Jessica Dyson, David Jones, Stefan G Hubscher, Paul Klenerman, David H Adams, Ye H Oo
Autoimmune hepatitis (AIH) is an immune-mediated liver disease currently treated by immunosuppressive medications with significant side effects. Thus, novel mechanistic treatments are greatly needed. We performed prospective deep immunophenotyping of blood immune cells in patients with acute AIH before and after corticosteroid therapy. Blood samples from 26 patients with acute AIH (United Kingdom-AIH Consortium) were phenotyped by flow cytometry at baseline and 4 months after starting corticosteroids. Pretreatment liver tissues were stained for forkhead box P3-positive (FOXP3POS ) regulatory T cells (Tregs), clusters of differentiation (CD)56POS natural killer (NK) cells, and chemokine (C-X-C motif) ligand 10...
April 2018: Hepatology communications
https://www.readbyqxmd.com/read/29617671/shp-2-is-dispensable-for-establishing-t-cell-exhaustion-and-for-pd-1-signaling-in-vivo
#18
Giorgia Rota, Charlène Niogret, Anh Thu Dang, Cristina Ramon Barros, Nicolas Pierre Fonta, Francesca Alfei, Leonor Morgado, Dietmar Zehn, Walter Birchmeier, Eric Vivier, Greta Guarda
In chronic infection and cancer, T cells acquire a dysfunctional state characterized by the expression of inhibitory receptors. In vitro studies implicated the phosphatase Shp-2 downstream of these receptors, including PD-1. However, whether Shp-2 is responsible in vivo for such dysfunctional responses remains elusive. To address this, we generated T cell-specific Shp-2-deficient mice. These mice did not show differences in controlling chronic viral infections. In this context, Shp-2-deleted CD8+ T lymphocytes expanded moderately better but were less polyfunctional than control cells...
April 3, 2018: Cell Reports
https://www.readbyqxmd.com/read/29602773/pd-l1-independent-mechanisms-control-the-resistance-of-melanoma-to-cd4-t-cell-adoptive-immunotherapy
#19
Stephen R Goding, Kyle A Wilson, Carolyn Rosinsky, Paul Andrew Antony
Immunotherapy is becoming the standard of care for melanoma. However, resistance to therapy is a major problem. Previously, we showed that tumor-specific, cytotoxic CD4+ T cells from tyrosinase-related protein 1 transgenic mice could overcome secondary resistance to recurring melanoma when anti-programmed cell death 1 ligand (PD-L1) checkpoint blockade was combined with either anti-lymphocyte-activated gene 3 (LAG-3) Abs or depletion of tumor-specific regulatory T (Treg ) cells. In this study, we show that PD-L1 expressed by the host, not B16 melanoma, plays a major role in the early stages of exhaustion or primary resistance...
March 30, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29553498/multiplexed-immunofluorescence-analysis-and-quantification-of-intratumoral-pd-1-tim-3-cd8-t-cells
#20
Clémence Granier, Emeline Vinatier, Elia Colin, Marion Mandavit, Charles Dariane, Virginie Verkarre, Lucie Biard, Rami El Zein, Corinne Lesaffre, Isabelle Galy-Fauroux, Hélène Roussel, Eléonore De Guillebon, Charlotte Blanc, Antonin Saldmann, Cécile Badoual, Alain Gey, Éric Tartour
Immune cells are important components of the tumor microenvironment and influence tumor growth and evolution at all stages of carcinogenesis. Notably, it is now well established that the immune infiltrate in human tumors can correlate with prognosis and response to therapy. The analysis of the immune infiltrate in the tumor microenvironment has become a major challenge for the classification of patients and the response to treatment. The co-expression of inhibitory receptors such as Program Cell Death Protein 1 (PD1; also known as CD279), Cytotoxic T Lymphocyte Associated Protein 4 (CTLA-4), T-Cell Immunoglobulin and Mucin Containing Protein-3 (Tim-3; also known as CD366), and Lymphocyte Activation Gene 3 (Lag-3; also known as CD223), is a hallmark of T cell exhaustion...
February 8, 2018: Journal of Visualized Experiments: JoVE
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