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Exhaustion clonal

Justin Eyquem, Jorge Mansilla-Soto, Theodoros Giavridis, Sjoukje J C van der Stegen, Mohamad Hamieh, Kristen M Cunanan, Ashlesha Odak, Mithat Gönen, Michel Sadelain
Chimeric antigen receptors (CARs) are synthetic receptors that redirect and reprogram T cells to mediate tumour rejection. The most successful CARs used to date are those targeting CD19 (ref. 2), which offer the prospect of complete remission in patients with chemorefractory or relapsed B-cell malignancies. CARs are typically transduced into the T cells of a patient using γ-retroviral vectors or other randomly integrating vectors, which may result in clonal expansion, oncogenic transformation, variegated transgene expression and transcriptional silencing...
February 22, 2017: Nature
Edward S Lee, Paul G Thomas, Jeff E Mold, Andrew J Yates
Characterisation of the T cell receptors (TCR) involved in immune responses is important for the design of vaccines and immunotherapies for cancer and autoimmune disease. The specificity of the interaction between the TCR heterodimer and its peptide-MHC ligand derives largely from the juxtaposed hypervariable CDR3 regions on the TCRα and TCRβ chains, and obtaining the paired sequences of these regions is a standard for functionally defining the TCR. A brute force approach to identifying the TCRs in a population of T cells is to use high-throughput single-cell sequencing, but currently this process remains costly and risks missing small clones...
January 2017: PLoS Computational Biology
Manuel Sala-Pérez, Tilman J Alpermann, Bernd Krock, Urban Tillmann
Harmful algal blooms are mainly caused by marine dinoflagellates and are known to produce potent toxins that may affect the ecosystem, human activities and health. Such events have increased in frequency and intensity worldwide in the past decades. Numerous processes involved in Global Change are amplified in the Arctic, but little is known about species specific responses of arctic dinoflagellates. The aim of this work was to perform an exhaustive morphological, phylogenetical and toxinological characterization of Greenland Protoceratium reticulatum and, in addition, to test the effect of temperature on growth and production of bioactive secondary metabolites...
May 2016: Harmful Algae
Pauline Gélin, Cécile Fauvelot, Vincent Mehn, Sophie Bureau, Héloïse Rouzé, Hélène Magalon
The scleractinian coral Pocillopora damicornis type β is known to present a mixed reproduction mode: through sexual reproduction, new genotypes are created, while asexual reproduction insures their propagation. In order to investigate the relative proportion of each reproduction mode in P. damicornis type β populations from Reunion Island, Indian Ocean, clonal propagation along the west coast was assessed through four sampling sites with increasing geographical distance between sites. Coral colonies were sampled either exhaustively, randomly or haphazardly within each site, and genotypic diversity was assessed using 13 microsatellite loci over a total of 510 P...
2017: PloS One
Arnab Ghosh, Melody Smith, Scott E James, Marco L Davila, Enrico Velardi, Kimon V Argyropoulos, Gertrude Gunset, Fabiana Perna, Fabiana M Kreines, Emily R Levy, Sophie Lieberman, Hillary V Jay, Andrea Z Tuckett, Johannes L Zakrzewski, Lisa Tan, Lauren F Young, Kate Takvorian, Jarrod A Dudakov, Robert R Jenq, Alan M Hanash, Ana Carolina F Motta, George F Murphy, Chen Liu, Andrea Schietinger, Michel Sadelain, Marcel R M van den Brink
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for hematological malignancies. However, graft-versus-host disease (GVHD) and relapse after allo-HSCT remain major impediments to the success of allo-HSCT. Chimeric antigen receptors (CARs) direct tumor cell recognition of adoptively transferred T cells. CD19 is an attractive CAR target, which is expressed in most B cell malignancies, as well as in healthy B cells. Clinical trials using autologous CD19-targeted T cells have shown remarkable promise in various B cell malignancies...
February 2017: Nature Medicine
Susan Pereira Ribeiro, Jeffrey M Milush, Edecio Cunha-Neto, Esper G Kallas, Jorge Kalil, Luiz Felipe D Passero, Peter W Hunt, Steven G Deeks, Douglas F Nixon, Devi SenGupta
Chronic HIV infection is characterized by increased immune activation and immunosenescence. p16 INK4a (p16) is a member of the cyclin-dependent kinase antagonist family that inhibits cellular proliferation, and its protein expression increases during normal chronological aging. However, some infectious diseases can increase the expression of this anti-proliferative protein, potentially accelerating immunological aging and dysfunction. In order to investigate the immunological aging in HIV patients, p16 protein expression was evaluated by flow cytometry, in T cell subsets in a cohort of chronically HIV-infected patients on and off ART as well as age-matched healthy controls...
2016: PloS One
Leslie A Crews, Larisa Balaian, Nathaniel P Delos Santos, Heather S Leu, Angela C Court, Elisa Lazzari, Anil Sadarangani, Maria A Zipeto, James J La Clair, Reymundo Villa, Anna Kulidjian, Rainer Storb, Sheldon R Morris, Edward D Ball, Michael D Burkart, Catriona H M Jamieson
Age-related human hematopoietic stem cell (HSC) exhaustion and myeloid-lineage skewing promote oncogenic transformation of hematopoietic progenitor cells into therapy-resistant leukemia stem cells (LSCs) in secondary acute myeloid leukemia (AML). While acquisition of clonal DNA mutations has been linked to increased rates of secondary AML for individuals older than 60 years, the contribution of RNA processing alterations to human hematopoietic stem and progenitor aging and LSC generation remains unclear. Comprehensive RNA sequencing and splice-isoform-specific PCR uncovered characteristic RNA splice isoform expression patterns that distinguished normal young and aged human stem and progenitor cells (HSPCs) from malignant myelodysplastic syndrome (MDS) and AML progenitors...
November 3, 2016: Cell Stem Cell
Eunseon Ahn, Ben Youngblood, Junghwa Lee, Judong Lee, Surojit Sarkar, Rafi Ahmed
UNLABELLED: PD-1 is an inhibitory receptor that has a major role in T cell dysfunction during chronic infections and cancer. While demethylation of the PD-1 promoter DNA is observed in exhausted T cells isolated from chronically infected individuals, little is known about when this stable demethylation of PD-1 promoter DNA is programmed during the course of a chronic infection. To assess if PD-1 promoter DNA demethylation is impacted by prolonged stimulation during effector phase of chronic infection, we adoptively transferred virus-specific day 8 effector CD8 T cells from mice infected with lymphocytic choriomeningitis virus (LCMV) clone 13 into recipient mice that had cleared an acute infection...
October 1, 2016: Journal of Virology
Claudia Lange, Richard J Weld, Murray P Cox, Rosie E Bradshaw, Kirstin L McLean, Alison Stewart, Johanna M Steyaert
Biological control agents (BCA) are beneficial organisms that are applied to protect plants from pests. Many fungi of the genus Trichoderma are successful BCAs but the underlying mechanisms are not yet fully understood. Trichoderma cf. atroviride strain LU132 is a remarkably effective BCA compared to T. cf. atroviride strain LU140 but these strains were found to be highly similar at the DNA sequence level. This unusual combination of phenotypic variability and high DNA sequence similarity between separately isolated strains prompted us to undertake a genome comparison study in order to identify DNA polymorphisms...
2016: PeerJ
Wilfred Ndifon, Jonathan Dushoff
Having a large number of sufficiently abundant T cell clones is important for adequate protection against diseases. However, as shown in this paper and elsewhere, between young adulthood and >70 y of age the effective clonal diversity of naive CD4/CD8 T cells found in human blood declines by a factor of >10. (Effective clonal diversity accounts for both the number and the abundance of T cell clones.) The causes of this observation are incompletely understood. A previous study proposed that it might result from the emergence of certain rare, replication-enhancing mutations in T cells...
June 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
C Giaccherini, C Verzeroli, M Marchetti, S Gamba, F Piras, L Russo, S Tessarolo, A Vignoli, G Finazzi, A Rambaldi, A Falanga
INTRODUCTION: Essential Thrombocythemia (ET) and Polycythemia Vera (PV) are two MPNs characterized by a "clonal" overproduction of one or more blood cell lines, hypercoagulability, and an increased incidence of thrombosis. ROTEM is a point of care global coagulation assay performed in whole blood, able to evaluate platelets and fibrinogen contributions to the clotting process. Until now few studies evaluated the thromboelastometry profile of MPN patients. AIM: This study assess the feasibility of using ROTEM to characterize the prothrombotic state of MPN patients and to evaluate whether the thromboelastometry profile varies according to mutational status and/or treatment, and is influenced by hemocromocytometric parameters...
April 2016: Thrombosis Research
Itay Tirosh, Benjamin Izar, Sanjay M Prakadan, Marc H Wadsworth, Daniel Treacy, John J Trombetta, Asaf Rotem, Christopher Rodman, Christine Lian, George Murphy, Mohammad Fallahi-Sichani, Ken Dutton-Regester, Jia-Ren Lin, Ofir Cohen, Parin Shah, Diana Lu, Alex S Genshaft, Travis K Hughes, Carly G K Ziegler, Samuel W Kazer, Aleth Gaillard, Kellie E Kolb, Alexandra-Chloé Villani, Cory M Johannessen, Aleksandr Y Andreev, Eliezer M Van Allen, Monica Bertagnolli, Peter K Sorger, Ryan J Sullivan, Keith T Flaherty, Dennie T Frederick, Judit Jané-Valbuena, Charles H Yoon, Orit Rozenblatt-Rosen, Alex K Shalek, Aviv Regev, Levi A Garraway
To explore the distinct genotypic and phenotypic states of melanoma tumors, we applied single-cell RNA sequencing (RNA-seq) to 4645 single cells isolated from 19 patients, profiling malignant, immune, stromal, and endothelial cells. Malignant cells within the same tumor displayed transcriptional heterogeneity associated with the cell cycle, spatial context, and a drug-resistance program. In particular, all tumors harbored malignant cells from two distinct transcriptional cell states, such that tumors characterized by high levels of the MITF transcription factor also contained cells with low MITF and elevated levels of the AXL kinase...
April 8, 2016: Science
H Suen, R Brown, S Yang, C Weatherburn, P J Ho, N Woodland, N Nassif, P Barbaro, C Bryant, D Hart, J Gibson, D Joshua
Tumour-induced dysfunction of cytotoxic T cells in patients with multiple myeloma (MM) may contribute to immune escape and be responsible for the lack of therapeutic efficacy of immune checkpoint blockade. We therefore investigated dysfunctional clonal T cells in MM and demonstrated immunosenescence but not exhaustion as a predominant feature. T-cell clones were detected in 75% of MM patients and their prognostic significance was revalidated in a new post-immunomodulatory drug cohort. The cells exhibited a senescent secretory effector phenotype: KLRG-1+/CD57+/CD160+/CD28-...
August 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Hongzhi Quan, Liangjuan Fang, Hao Pan, Zhiyuan Deng, Shan Gao, Ousheng Liu, Yuehong Wang, Yanjia Hu, Xiaodan Fang, Zhigang Yao, Feng Guo, Ruohuang Lu, Kun Xia, Zhangui Tang
Lymphocyte infiltrates have been observed in the microenvironment of oral cancer; however, little is known about whether the immune response of the lymphocyte infiltrate affects tumor biology. For a deeper understanding of the role of the infiltrating-lymphocytes in oral squamous cell carcinoma (OSCC), we characterized the lymphocyte infiltrate repertoires and defined their features. Immunohistochemistry revealed considerable T and B cell infiltrates and lymphoid follicles with germinal center-like structures within the tumor microenvironment...
June 15, 2016: International Journal of Cancer. Journal International du Cancer
Nicole Malandro, Sadna Budhu, Nicholas F Kuhn, Cailian Liu, Judith T Murphy, Czrina Cortez, Hong Zhong, Xia Yang, Gabrielle Rizzuto, Grégoire Altan-Bonnet, Taha Merghoub, Jedd D Wolchok
Current approaches to cancer immunotherapy aim to engage the natural T cell response against tumors. One limitation is the elimination of self-antigen-specific T cells from the immune repertoire. Using a system in which precursor frequency can be manipulated in a murine melanoma model, we demonstrated that the clonal abundance of CD4(+) T cells specific for self-tumor antigen positively correlated with antitumor efficacy. At elevated precursor frequencies, intraclonal competition impaired initial activation and overall expansion of the tumor-specific CD4(+) T cell population...
January 19, 2016: Immunity
Wesley Mattheus, Germaine Hanquet, Jean-Marc Collard, Raymond Vanhoof, Sophie Bertrand
BACKGROUND: Invasive meningococcal disease (IMD) is a major cause of bacterial meningitides and septicaemia. This study shows the results of the laboratory-based surveillance of IMD in Belgium over the period 1997-2012. METHODS: The results are based on microbiological and molecular laboratory surveillance of 2997 clinical isolates of N. meningitides received by the Belgian Meningococcal Reference Centre (BMRC) over the period 1997-2012. RESULTS: Serogroup B has always been a major cause of meningococcal disease in Belgium, with P3...
2015: PloS One
Francesco Forconi, Paul Moss
Immune dysregulation is a cardinal feature of chronic lymphocytic leukemia (CLL) from its early stage and worsens during clinical observation, even in absence of disease progression. Although the mechanisms remain unclear, new insights are emerging into the complex relationship between the CLL clone and its immune environment. T cells are increased in early-stage disease and show progressive accumulation and exhaustion. The mechanisms that drive this expansion may include auto-antigens involved in the original clonal expansion...
July 30, 2015: Blood
Kais Hamza, Peter Jagers, Fima C Klebaner
Comprehensive models of stochastic, clonally reproducing populations are defined in terms of general branching processes, allowing birth during maternal life, as for higher organisms, or by splitting, as in cell division. The populations are assumed to start small, by mutation or immigration, reproduce supercritically while smaller than the habitat carrying capacity but subcritically above it. Such populations establish themselves with a probability wellknown from branching process theory. Once established, they grow up to a band around the carrying capacity in a time that is logarithmic in the latter, assumed large...
March 2016: Journal of Mathematical Biology
Yvonne Suessmuth, Rithun Mukherjee, Benjamin Watkins, Divya T Koura, Knut Finstermeier, Cindy Desmarais, Linda Stempora, John T Horan, Amelia Langston, Muna Qayed, Hanna J Khoury, Audrey Grizzle, Jennifer A Cheeseman, Jason A Conger, Jennifer Robertson, Aneesah Garrett, Allan D Kirk, Edmund K Waller, Bruce R Blazar, Aneesh K Mehta, Harlan S Robins, Leslie S Kean
Although cytomegalovirus (CMV) reactivation has long been implicated in posttransplant immune dysfunction, the molecular mechanisms that drive this phenomenon remain undetermined. To address this, we combined multiparameter flow cytometric analysis and T-cell subpopulation sorting with high-throughput sequencing of the T-cell repertoire, to produce a thorough evaluation of the impact of CMV reactivation on T-cell reconstitution after unrelated-donor hematopoietic stem cell transplant. We observed that CMV reactivation drove a >50-fold specific expansion of Granzyme B(high)/CD28(low)/CD57(high)/CD8(+) effector memory T cells (Tem) and resulted in a linked contraction of all naive T cells, including CD31(+)/CD4(+) putative thymic emigrants...
June 18, 2015: Blood
Filippo Calzolari, Julia Michel, Emily Violette Baumgart, Fabian Theis, Magdalena Götz, Jovica Ninkovic
We analyzed the progeny of individual neural stem cells (NSCs) of the mouse adult subependymal zone (SEZ) in vivo and found a markedly fast lineage amplification, as well as limited NSC self-renewal and exhaustion in a few weeks. We further unraveled the mechanisms of neuronal subtype generation, finding that a higher proportion of NSCs were dedicated to generate deep granule cells in the olfactory bulb and that larger clones were produced by these NSCs.
April 2015: Nature Neuroscience
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