Publications
2014
Acker, Aline Van; Filtjens, Jessica; Welden, Sophie Van; Taveirne, Sylvie; Ammel, Els Van; Vanhees, Mandy; Devisscher, Lindsey; Kerre, Tessa; Taghon, Tom; Vandekerckhove, Bart; Plum, Jean; Leclercq, Georges
In: PloS one, vol. 9, pp. e110015, 2014, ISSN: 1932-6203.
@article{VanAcker2014,
title = {Ly49E expression on CD8αα-expressing intestinal intraepithelial lymphocytes plays no detectable role in the development and progression of experimentally induced inflammatory bowel diseases.},
author = {Aline Van Acker and Jessica Filtjens and Sophie Van Welden and Sylvie Taveirne and Els Van Ammel and Mandy Vanhees and Lindsey Devisscher and Tessa Kerre and Tom Taghon and Bart Vandekerckhove and Jean Plum and Georges Leclercq},
doi = {10.1371/journal.pone.0110015},
issn = {1932-6203},
year = {2014},
date = {2014-01-01},
journal = {PloS one},
volume = {9},
pages = {e110015},
abstract = {The Ly49E NK receptor is a unique inhibitory receptor, presenting with a high degree of conservation among mouse strains and expression on both NK cells and intraepithelial-localised T cells. Amongst intraepithelial-localised T cells, the Ly49E receptor is abundantly expressed on CD8αα-expressing innate-like intestinal intraepithelial lymphocytes (iIELs), which contribute to front-line defense at the mucosal barrier. Inflammatory bowel diseases (IBDs), encompassing Crohn's disease and ulcerative colitis, have previously been suggested to have an autoreactive origin and to evolve from a dysbalance between regulatory and effector functions in the intestinal immune system. Here, we made use of Ly49E-deficient mice to characterize the role of Ly49E receptor expression on CD8αα-expressing iIELs in the development and progression of IBD. For this purpose we used the dextran sodium sulphate (DSS)- and trinitrobenzenesulfonic-acid (TNBS)-induced colitis models, and the TNFΔARE ileitis model. We show that Ly49E is expressed on a high proportion of CD8αα-positive iIELs, with higher expression in the colon as compared to the small intestine. However, Ly49E expression on small intestinal and colonic iIELs does not influence the development or progression of inflammatory bowel diseases.},
keywords = {},
pubstate = {epublish},
tppubtype = {article}
}
Ferreiro, Julio Finalet; Rouhigharabaei, Leila; Urbankova, Helena; van der Krogt, Jo-Anne; Michaux, Lucienne; Shetty, Shashirekha; Krenacs, Laszlo; Tousseyn, Thomas; Paepe, Pascale De; Uyttebroeck, Anne; Verhoef, Gregor; Taghon, Tom; Vandenberghe, Peter; Cools, Jan; Wlodarska, Iwona
Integrative genomic and transcriptomic analysis identified candidate genes implicated in the pathogenesis of hepatosplenic T-cell lymphoma. Journal Article
In: PloS one, vol. 9, pp. e102977, 2014, ISSN: 1932-6203.
@article{FinaletFerreiro2014,
title = {Integrative genomic and transcriptomic analysis identified candidate genes implicated in the pathogenesis of hepatosplenic T-cell lymphoma.},
author = {Julio Finalet Ferreiro and Leila Rouhigharabaei and Helena Urbankova and Jo-Anne van der Krogt and Lucienne Michaux and Shashirekha Shetty and Laszlo Krenacs and Thomas Tousseyn and Pascale De Paepe and Anne Uyttebroeck and Gregor Verhoef and Tom Taghon and Peter Vandenberghe and Jan Cools and Iwona Wlodarska},
doi = {10.1371/journal.pone.0102977},
issn = {1932-6203},
year = {2014},
date = {2014-01-01},
journal = {PloS one},
volume = {9},
pages = {e102977},
abstract = {Hepatosplenic T-cell lymphoma (HSTL) is an aggressive lymphoma cytogenetically characterized by isochromosome 7q [i(7)(q10)], of which the molecular consequences remain unknown. We report here results of an integrative genomic and transcriptomic (expression microarray and RNA-sequencing) study of six i(7)(q10)-positive HSTL cases, including HSTL-derived cell line (DERL-2), and three cases with ring 7 [r(7)], the recently identified rare variant aberration. Using high resolution array CGH, we profiled all cases and mapped the common deleted region (CDR) at 7p22.1p14.1 (34.88 Mb; 3506316-38406226 bp) and the common gained region (CGR) at 7q22.11q31.1 (38.77 Mb; 86259620-124892276 bp). Interestingly, CDR spans a smaller region of 13 Mb (86259620-99271246 bp) constantly amplified in cases with r(7). In addition, we found that TCRG (7p14.1) and TCRB (7q32) are involved in formation of r(7), which seems to be a byproduct of illegitimate somatic rearrangement of both loci. Further transcriptomic analysis has not identified any CDR-related candidate tumor suppressor gene. Instead, loss of 7p22.1p14.1 correlated with an enhanced expression of CHN2 (7p14.1) and the encoded β2-chimerin. Gain and amplification of 7q22.11q31.1 are associated with an increased expression of several genes postulated to be implicated in cancer, including RUNDC3B, PPP1R9A and ABCB1, a known multidrug resistance gene. RNA-sequencing did not identify any disease-defining mutation or gene fusion. Thus, chromosome 7 imbalances remain the only driver events detected in this tumor. We hypothesize that the Δ7p22.1p14.1-associated enhanced expression of CHN2/β2-chimerin leads to downmodulation of the NFAT pathway and a proliferative response, while upregulation of the CGR-related genes provides growth advantage for neoplastic δγT-cells and underlies their intrinsic chemoresistance. Finally, our study confirms the previously described gene expression profile of HSTL and identifies a set of 24 genes, including three located on chromosome 7 (CHN2, ABCB1 and PPP1R9A), distinguishing HSTL from other malignancies.},
keywords = {},
pubstate = {epublish},
tppubtype = {article}
}
Filtjens, Jessica; Foquet, Lander; Taveirne, Sylvie; Ammel, Els Van; Vanhees, Mandy; Acker, Aline Van; Kerre, Tessa; Taghon, Tom; Vandekerckhove, Bart; Plum, Jean; den Steen, Philippe E Van; Leclercq, Georges
In: PloS one, vol. 9, pp. e87463, 2014, ISSN: 1932-6203.
@article{Filtjens2014,
title = {Contribution of the Ly49E natural killer receptor in the immune response to Plasmodium berghei infection and control of hepatic parasite development.},
author = {Jessica Filtjens and Lander Foquet and Sylvie Taveirne and Els Van Ammel and Mandy Vanhees and Aline Van Acker and Tessa Kerre and Tom Taghon and Bart Vandekerckhove and Jean Plum and Philippe E Van den Steen and Georges Leclercq},
doi = {10.1371/journal.pone.0087463},
issn = {1932-6203},
year = {2014},
date = {2014-01-01},
journal = {PloS one},
volume = {9},
pages = {e87463},
abstract = {Natural killer (NK) cells have different roles in the host response against Plasmodium-induced malaria depending on the stage of infection. Liver NK cells have a protective role during the initial hepatic stage of infection by production of the TH1-type cytokines IFN-γ and TNF-α. In the subsequent erythrocytic stage of infection, NK cells also induce protection through Th1-type cytokines but, in addition, may also promote development of cerebral malaria via CXCR3-induction on CD8(+) T cells resulting in migration of these cells to the brain. We have recently shown that the regulatory Ly49E NK receptor is expressed on liver NK cells in particular. The main objective of this study was therefore to examine the role of Ly49E expression in the immune response upon Plasmodium berghei ANKA infection, for which we compared wild type (WT) to Ly49E knockout (KO) mice. We show that the parasitemia was higher at the early stage, i.e. at days 6-7 of Plasmodium berghei ANKA infection in Ly49E KO mice, which correlated with lower induction of CD69, IFN-γ and TNF-α in DX5(-) liver NK cells at day 5 post-infection. At later stages, these differences faded. There was also no difference in the kinetics and the percentage of cerebral malaria development and in lymphocyte CXCR3 expression in WT versus Ly49E KO mice. Collectively, we show that the immune response against Plasmodium berghei ANKA infection is not drastically affected in Ly49E KO mice. Although NK cells play a crucial role in Plasmodium infection and Ly49E is highly expressed on liver NK cells, the Ly49E NK receptor only has a temporarily role in the immune control of this parasite.},
keywords = {},
pubstate = {epublish},
tppubtype = {article}
}
2013
Nuffel, Anouk Van; Ariën, Kevin K; Stove, Veronique; Schindler, Michael; O'Neill, Eduardo; Schmökel, Jan; de Walle, Inge Van; Naessens, Evelien; Vanderstraeten, Hanne; Landeghem, Kathleen Van; Taghon, Tom; Pulkkinen, Kati; Saksela, Kalle; Garcia, Victor J; Fackler, Oliver T; Kirchhoff, Frank; Verhasselt, Bruno
Primate lentiviral Nef proteins deregulate T-cell development by multiple mechanisms. Journal Article
In: Retrovirology, vol. 10, pp. 137, 2013, ISSN: 1742-4690.
@article{VanNuffel2013,
title = {Primate lentiviral Nef proteins deregulate T-cell development by multiple mechanisms.},
author = {Anouk Van Nuffel and Kevin K Ariën and Veronique Stove and Michael Schindler and Eduardo O'Neill and Jan Schmökel and Inge Van de Walle and Evelien Naessens and Hanne Vanderstraeten and Kathleen Van Landeghem and Tom Taghon and Kati Pulkkinen and Kalle Saksela and Victor J Garcia and Oliver T Fackler and Frank Kirchhoff and Bruno Verhasselt},
doi = {10.1186/1742-4690-10-137},
issn = {1742-4690},
year = {2013},
date = {2013-11-01},
journal = {Retrovirology},
volume = {10},
pages = {137},
abstract = {A nef gene is present in all primate lentiviral genomes and is important for high viral loads and progression to AIDS in human or experimental macaque hosts of HIV or SIV, respectively. In these hosts, infection of the thymus results in a decreased output of naive T cells that may contribute to the development of immunodeficiency. We have previously shown that HIV-1 subtype B Nef proteins can block human T-cell development. However, the underlying mechanism(s) and the conservation of this Nef function between different groups of HIV and SIV remained to be determined. We investigated whether reduction of thymic output is a conserved function of highly divergent lentiviral Nef proteins including those from both types of human immunodeficiency viruses (HIV-1 and HIV-2), their direct simian counterparts (SIVcpz, SIVgor and SIVsmm, respectively), and some additional SIV strains. We found that expression of most of these nef alleles in thymocyte progenitors impaired T-cell development and reduced thymic output. For HIV-1 Nef, binding to active p21 protein (Cdc42/Rac)-activated kinase (PAK2) was a major determinant of this function. In contrast, selective disruption of PAK2 binding did not eliminate the effect on T-cell development of SIVmac239 Nef, as was shown by expressing mutants in a newly discovered PAK2 activating structural motif (PASM) constituted by residues I117, H121, T218 and Y221, as well as previously described mutants. Rather, down-modulation of cell surface CD3 was sufficient for reduced thymic output by SIVmac Nef, while other functions of SIV Nefs contributed. Our results indicate that primate lentiviral Nef proteins impair development of thymocyte precursors into T cells in multiple ways. The interaction of HIV-1 Nef with active PAK2 by HIV-1 seem to be most detrimental, and downregulation of CD3 by HIV-2 and most SIV Nef proteins sufficient for reduced thymic output. Since the reduction of thymic output by Nef is a conserved property of divergent lentiviruses, it is likely to be relevant for peripheral T-cell depletion in poorly adapted primate lentiviral infections.},
keywords = {},
pubstate = {epublish},
tppubtype = {article}
}
Filtjens, Jessica; Taveirne, Sylvie; Acker, Aline Van; Ammel, Els Van; Vanhees, Mandy; Kerre, Tessa; Taghon, Tom; Vandekerckhove, Bart; Plum, Jean; Leclercq, Georges
Abundant stage-dependent Ly49E expression by liver NK cells is not essential for their differentiation and function. Journal Article
In: Journal of leukocyte biology, vol. 93, pp. 699–711, 2013, ISSN: 1938-3673.
@article{Filtjens2013,
title = {Abundant stage-dependent Ly49E expression by liver NK cells is not essential for their differentiation and function.},
author = {Jessica Filtjens and Sylvie Taveirne and Aline Van Acker and Els Van Ammel and Mandy Vanhees and Tessa Kerre and Tom Taghon and Bart Vandekerckhove and Jean Plum and Georges Leclercq},
doi = {10.1189/jlb.0812378},
issn = {1938-3673},
year = {2013},
date = {2013-05-01},
journal = {Journal of leukocyte biology},
volume = {93},
pages = {699--711},
abstract = {The NKR Ly49E has several unique characteristics. Unlike most NKRs, Ly49E is highly expressed on fetal NK cells, whereas expression is decreased on bone marrow-derived NK cells in adult mice. To investigate a possible role for Ly49E in NK cell differentiation and function, we have generated an Ly49E KO mouse. Our results show that bone marrow and splenic NK cells are present in normal numbers in Ly49E KO mice, expressing an unaltered panel of NKRs and differentiation markers. Furthermore, cytokine production and cytotoxicity by these cells are unaffected. Surprisingly, WT DX5(-) liver NK cells express high Ly49E levels in fetal and adult mice. Ly49E(+)DX5(-) liver NK cells transferred into Rag-2(-/-)/gc(-/-) mice maintain high Ly49E expression in the liver and differentiate into DX5(+) NK cells in spleen and bone marrow. Ly49E expression is not crucial for liver NK cell differentiation during ontogeny, as the DX5(-)/DX5(+) ratio, the NKR repertoire, and the granzyme B and TRAIL levels are comparable in Ly49E KO versus WT mice, except for lower TRAIL expression on DX5(-) liver NK cells in 20-day-old mice. The TRAIL-, perforin-, and FasL-mediated cytolysis by liver NK cells is unaffected in Ly49E KO mice. Collectively, we show that in addition to high Ly49E expression on fetal NK cells versus low Ly49E expression on conventional NK cells in adult life, Ly49E remains highly expressed on DX5(-) liver NK cells. However, Ly49E expression does not have a crucial role in differentiation and/or function of these NK cells.},
keywords = {},
pubstate = {ppublish},
tppubtype = {article}
}
de Walle, Inge Van; Waegemans, Els; Medts, Jelle De; Smet, Greet De; Smedt, Magda De; Snauwaert, Sylvia; Vandekerckhove, Bart; Kerre, Tessa; Leclercq, Georges; Plum, Jean; Gridley, Thomas; Wang, Tao; Koch, Ute; Radtke, Freddy; Taghon, Tom
Specific Notch receptor-ligand interactions control human TCR-αβ/γδ development by inducing differential Notch signal strength. Journal Article
In: The Journal of experimental medicine, vol. 210, pp. 683–697, 2013, ISSN: 1540-9538.
@article{VandeWalle2013,
title = {Specific Notch receptor-ligand interactions control human TCR-αβ/γδ development by inducing differential Notch signal strength.},
author = {Inge Van de Walle and Els Waegemans and Jelle De Medts and Greet De Smet and Magda De Smedt and Sylvia Snauwaert and Bart Vandekerckhove and Tessa Kerre and Georges Leclercq and Jean Plum and Thomas Gridley and Tao Wang and Ute Koch and Freddy Radtke and Tom Taghon},
doi = {10.1084/jem.20121798},
issn = {1540-9538},
year = {2013},
date = {2013-04-01},
journal = {The Journal of experimental medicine},
volume = {210},
pages = {683--697},
abstract = {In humans, high Notch activation promotes γδ T cell development, whereas lower levels promote αβ-lineage differentiation. How these different Notch signals are generated has remained unclear. We show that differential Notch receptor-ligand interactions mediate this process. Whereas Delta-like 4 supports both TCR-αβ and -γδ development, Jagged1 induces mainly αβ-lineage differentiation. In contrast, Jagged2-mediated Notch activation primarily results in γδ T cell development and represses αβ-lineage differentiation by inhibiting TCR-β formation. Consistently, TCR-αβ T cell development is rescued through transduction of a TCR-β transgene. Jagged2 induces the strongest Notch signal through interactions with both Notch1 and Notch3, whereas Delta-like 4 primarily binds Notch1. In agreement, Notch3 is a stronger Notch activator and only supports γδ T cell development, whereas Notch1 is a weaker activator supporting both TCR-αβ and -γδ development. Fetal thymus organ cultures in JAG2-deficient thymic lobes or with Notch3-blocking antibodies confirm the importance of Jagged2/Notch3 signaling in human TCR-γδ differentiation. Our findings reveal that differential Notch receptor-ligand interactions mediate human TCR-αβ and -γδ T cell differentiation and provide a mechanistic insight into the high Notch dependency of human γδ T cell development.},
keywords = {},
pubstate = {ppublish},
tppubtype = {article}
}
Broeck, Tina Van Den; Ammel, Els Van; Delforche, Maarten; Taveirne, Sylvie; Kerre, Tessa; Vandekerckhove, Bart; Taghon, Tom; Plum, Jean; Leclercq, Georges
Differential Ly49e expression pathways in resting versus TCR-activated intraepithelial γδ T cells. Journal Article
In: Journal of immunology (Baltimore, Md. : 1950), vol. 190, pp. 1982–1990, 2013, ISSN: 1550-6606.
@article{VanDenBroeck2013,
title = {Differential Ly49e expression pathways in resting versus TCR-activated intraepithelial γδ T cells.},
author = {Tina Van Den Broeck and Els Van Ammel and Maarten Delforche and Sylvie Taveirne and Tessa Kerre and Bart Vandekerckhove and Tom Taghon and Jean Plum and Georges Leclercq},
doi = {10.4049/jimmunol.1200354},
issn = {1550-6606},
year = {2013},
date = {2013-03-01},
journal = {Journal of immunology (Baltimore, Md. : 1950)},
volume = {190},
pages = {1982--1990},
abstract = {The Ly49 NK receptor family in mice is composed of several members that recognize MHC class I (MHC-I) or MHC-I-related molecules. We and others have shown before that Ly49E is a unique member, with a different expression pattern on NK cells and being triggered by the non-MHC-I-related protein urokinase plasminogen activator. Among the entire Ly49 receptor family, Ly49E is the only Ly49 member expressed by epidermal-localized γδ T cells and their fetal thymic TCRγδ precursors, and it is the most abundantly expressed member on intestinal intraepithelial γδ T cell lymphocytes. In this study, we provide mechanistic insights into the regulation of Ly49e expression in γδ T cells. First, we demonstrate that TCR-mediated activation of intraepithelial γδ T cells significantly increases Ly49E expression. This results from de novo Ly49E expression and is highly selective, because no other Ly49 family members are induced. TCR-mediated Ly49E induction is a conserved feature of skin- and gut-residing intraepithelial-localized γδ T cell subsets, whereas it is not observed in spleen γδ T cells. By investigating Ly49e promoter activities and lymphotoxin (LT) αβ dependency in resting versus TCR-activated intraepithelial γδ T cells, we reveal two separate regulatory pathways for Ly49E expression, as follows: a LTαβ-dependent pathway leading to basal Ly49E expression in resting cells that is induced by Pro2-mediated Ly49e transcription, and a LTαβ-independent pathway leading to elevated, Pro3-driven Ly49E expression in TCR-stimulated cells.},
keywords = {},
pubstate = {ppublish},
tppubtype = {article}
}
2012
Snauwaert, Sylvia; Vanhee, Stijn; Goetgeluk, Glenn; Verstichel, Greet; Caeneghem, Yasmine Van; Velghe, Imke; Philippé, Jan; Berneman, Zwi N; Plum, Jean; Taghon, Tom; Leclercq, Georges; Thielemans, Kris; Kerre, Tessa; Vandekerckhove, Bart
RHAMM/HMMR (CD168) is not an ideal target antigen for immunotherapy of acute myeloid leukemia. Journal Article
In: Haematologica, vol. 97, pp. 1539–1547, 2012, ISSN: 1592-8721.
@article{Snauwaert2012,
title = {RHAMM/HMMR (CD168) is not an ideal target antigen for immunotherapy of acute myeloid leukemia.},
author = {Sylvia Snauwaert and Stijn Vanhee and Glenn Goetgeluk and Greet Verstichel and Yasmine Van Caeneghem and Imke Velghe and Jan Philippé and Zwi N Berneman and Jean Plum and Tom Taghon and Georges Leclercq and Kris Thielemans and Tessa Kerre and Bart Vandekerckhove},
doi = {10.3324/haematol.2012.065581},
issn = {1592-8721},
year = {2012},
date = {2012-10-01},
journal = {Haematologica},
volume = {97},
pages = {1539--1547},
abstract = {Criteria for good candidate antigens for immunotherapy of acute myeloid leukemia are high expression on leukemic stem cells in the majority of patients with acute myeloid leukemia and low or no expression in vital tissues. It was shown in vaccination trials that Receptor for Hyaluronic Acid Mediated Motility (RHAMM/HMMR) generates cellular immune responses in patients with acute myeloid leukemia and that these responses correlate with clinical benefit. It is not clear however whether this response actually targets the leukemic stem cell, especially since it was reported that RHAMM is expressed maximally during the G2/M phase of the cell cycle. In addition, tumor specificity of RHAMM expression remains relatively unexplored. Blood, leukapheresis and bone marrow samples were collected from both acute myeloid leukemia patients and healthy controls. RHAMM expression was assessed at protein and mRNA levels on various sorted populations, either fresh or after manipulation. High levels of RHAMM were expressed by CD34(+)CD38(+) and CD34(-) acute myeloid leukemia blasts. However, only baseline expression of RHAMM was measured in CD34(+)CD38(-) leukemic stem cells, and was not different from that in CD34(+)CD38(-) hematopoietic stem cells from healthy controls. RHAMM was significantly up-regulated in CD34(+) cells from healthy donors during in vitro expansion and during in vivo engraftment. Finally, we demonstrated an explicit increase in the expression level of RHAMM after in vitro activation of T cells. RHAMM does not fulfill the criteria of an ideal target antigen for immunotherapy of acute myeloid leukemia. RHAMM expression in leukemic stem cells does not differ significantly from the expression in hematopoietic stem cells from healthy controls. RHAMM expression in proliferating CD34+ cells of healthy donors and activated T cells further compromises RHAMM-specific T-cell-mediated immunotherapy.},
keywords = {},
pubstate = {ppublish},
tppubtype = {article}
}
Vermeire, Jolien; Naessens, Evelien; Vanderstraeten, Hanne; Landi, Alessia; Iannucci, Veronica; Nuffel, Anouk Van; Taghon, Tom; Pizzato, Massimo; Verhasselt, Bruno
In: PloS one, vol. 7, pp. e50859, 2012, ISSN: 1932-6203.
@article{Vermeire2012,
title = {Quantification of reverse transcriptase activity by real-time PCR as a fast and accurate method for titration of HIV, lenti- and retroviral vectors.},
author = {Jolien Vermeire and Evelien Naessens and Hanne Vanderstraeten and Alessia Landi and Veronica Iannucci and Anouk Van Nuffel and Tom Taghon and Massimo Pizzato and Bruno Verhasselt},
doi = {10.1371/journal.pone.0050859},
issn = {1932-6203},
year = {2012},
date = {2012-01-01},
journal = {PloS one},
volume = {7},
pages = {e50859},
abstract = {Quantification of retroviruses in cell culture supernatants and other biological preparations is required in a diverse spectrum of laboratories and applications. Methods based on antigen detection, such as p24 for HIV, or on genome detection are virus specific and sometimes suffer from a limited dynamic range of detection. In contrast, measurement of reverse transcriptase (RT) activity is a generic method which can be adapted for higher sensitivity using real-time PCR quantification (qPCR-based product-enhanced RT (PERT) assay). We present an evaluation of a modified SYBR Green I-based PERT assay (SG-PERT), using commercially available reagents such as MS2 RNA and ready-to-use qPCR mixes. This assay has a dynamic range of 7 logs, a sensitivity of 10 nU HIV-1 RT and outperforms p24 ELISA for HIV titer determination by lower inter-run variation, lower cost and higher linear range. The SG-PERT values correlate with transducing and infectious units in HIV-based viral vector and replication-competent HIV-1 preparations respectively. This assay can furthermore quantify Moloney Murine Leukemia Virus-derived vectors and can be performed on different instruments, such as Roche Lightcycler® 480 and Applied Biosystems ABI 7300. We consider this test to be an accurate, fast and relatively cheap method for retroviral quantification that is easily implemented for use in routine and research laboratories.},
keywords = {},
pubstate = {ppublish},
tppubtype = {article}
}
Taghon, Tom; Waegemans, Els; de Walle, Inge Van
Notch signaling during human T cell development. Journal Article
In: Current topics in microbiology and immunology, vol. 360, pp. 75–97, 2012, ISSN: 0070-217X.
@article{Taghon2012,
title = {Notch signaling during human T cell development.},
author = {Tom Taghon and Els Waegemans and Inge Van de Walle},
doi = {10.1007/82_2012_230},
issn = {0070-217X},
year = {2012},
date = {2012-01-01},
journal = {Current topics in microbiology and immunology},
volume = {360},
pages = {75--97},
abstract = {Notch signaling is critical during multiple stages of T cell development in both mouse and human. Evidence has emerged in recent years that this pathway might regulate T-lineage differentiation differently between both species. Here, we review our current understanding of how Notch signaling is activated and used during human T cell development. First, we set the stage by describing the developmental steps that make up human T cell development before describing the expression profiles of Notch receptors, ligands, and target genes during this process. To delineate stage-specific roles for Notch signaling during human T cell development, we subsequently try to interpret the functional Notch studies that have been performed in light of these expression profiles and compare this to its suggested role in the mouse.},
keywords = {},
pubstate = {ppublish},
tppubtype = {article}
}
2011
Colvenaer, Veerle De; Taveirne, Sylvie; Delforche, Maarten; Smedt, Magda De; Vandekerckhove, Bart; Taghon, Tom; Boon, Louis; Plum, Jean; Leclercq, Georges
CD27-deficient mice show normal NK-cell differentiation but impaired function upon stimulation. Journal Article
In: Immunology and cell biology, vol. 89, pp. 803–811, 2011, ISSN: 1440-1711.
@article{DeColvenaer2011,
title = {CD27-deficient mice show normal NK-cell differentiation but impaired function upon stimulation.},
author = {Veerle De Colvenaer and Sylvie Taveirne and Maarten Delforche and Magda De Smedt and Bart Vandekerckhove and Tom Taghon and Louis Boon and Jean Plum and Georges Leclercq},
doi = {10.1038/icb.2010.171},
issn = {1440-1711},
year = {2011},
date = {2011-10-01},
journal = {Immunology and cell biology},
volume = {89},
pages = {803--811},
abstract = {Natural killer (NK) cells are part of the first line defense against tumors, parasites and virus-infected cells. Therefore, factors that control NK-cell numbers and their function are important. CD27 is constitutively expressed on NK cells and its expression correlates with sequential phases in NK-cell development, discriminating phenotypically and functionally different subsets within the NK-cell population. Although CD27 has been described to have an important regulatory role in effector and memory T and B lymphocytes, its role in NK-cell biology remains to be addressed. In this study, we used CD27(-/-) mice to investigate the role of CD27 in NK-cell development and function, both during the resting state and upon stimulation. The results show that NK-cell numbers are not impaired in CD27(-/-) mice. Moreover, CD27(-/-) NK cells reach full phenotypic maturity, evidenced by normal expression of CD49b, CD43 and CD11b. Expression of activating receptors is unaltered, whereas expression of several inhibitory receptors is increased. Cytotoxicity and interferon-γ production by NK cells from CD27(-/-) mice in the resting state are normal. However, upon in vivo anti-CD40- or poly-I:C-mediated activation, or in vitro interleukin-15 priming plus anti-NKp46 stimulation, the absence of CD27 results in decreased cytolytic activity and cytokine production by spleen and liver NK cells. In conclusion, this study demonstrates that CD27 is dispensable for the development of functional NK cells. However, upon stimulation of NK cells, CD27 displays an important role in their activation and functionality.},
keywords = {},
pubstate = {ppublish},
tppubtype = {article}
}
Weer, An De; der Meulen, Joni Van; Rondou, Pieter; Taghon, Tom; Konrad, Torsten A; Preter, Katleen De; Mestdagh, Pieter; Maerken, Tom Van; Roy, Nadine Van; Jeison, Marta; Yaniv, Isaac; Cauwelier, Barbara; Noens, Lucien; Poirel, Hélène-Antoine; Vandenberghe, Peter; Lambert, Frédéric; Paepe, Anne De; Sánchez, Maria García; Odero, Maria; Verhasselt, Bruno; Philippé, Jan; Vandesompele, Joke; Wieser, Rotraud; Dastugue, Nicole; Vlierberghe, Pieter Van; Poppe, Bruce; Speleman, Frank
EVI1-mediated down regulation of MIR449A is essential for the survival of EVI1 positive leukaemic cells. Journal Article
In: British journal of haematology, vol. 154, pp. 337–348, 2011, ISSN: 1365-2141.
@article{DeWeer2011,
title = {EVI1-mediated down regulation of MIR449A is essential for the survival of EVI1 positive leukaemic cells.},
author = {An De Weer and Joni Van der Meulen and Pieter Rondou and Tom Taghon and Torsten A Konrad and Katleen De Preter and Pieter Mestdagh and Tom Van Maerken and Nadine Van Roy and Marta Jeison and Isaac Yaniv and Barbara Cauwelier and Lucien Noens and Hélène-Antoine Poirel and Peter Vandenberghe and Frédéric Lambert and Anne De Paepe and Maria García Sánchez and Maria Odero and Bruno Verhasselt and Jan Philippé and Joke Vandesompele and Rotraud Wieser and Nicole Dastugue and Pieter Van Vlierberghe and Bruce Poppe and Frank Speleman},
doi = {10.1111/j.1365-2141.2011.08737.x},
issn = {1365-2141},
year = {2011},
date = {2011-08-01},
journal = {British journal of haematology},
volume = {154},
pages = {337--348},
abstract = {Chromosomal rearrangements involving the MECOM (MDS1 and EVI1 complex) locus are recurrent genetic events in myeloid leukaemia and are associated with poor prognosis. In this study, we assessed the role of MECOM locus protein EVI1 in the transcriptional regulation of microRNAs (miRNAs) involved in the leukaemic phenotype. For this, we profiled expression of 366 miRNAs in 38 MECOM-rearranged patient samples, normal bone marrow controls and MECOM (EVI1) knock down/re-expression models. Cross-comparison of these miRNA expression profiling data showed that MECOM rearranged leukaemias are characterized by down regulation of MIR449A. Reconstitution of MIR449A expression in MECOM-rearranged cell line models induced apoptosis resulting in a strong decrease in cell viability. These effects might be mediated in part by MIR449A regulation of NOTCH1 and BCL2, which are shown here to be bona fide MIR449A targets. Finally, we confirmed that MIR449A repression is mediated through direct promoter occupation of the EVI1 transcriptional repressor. In conclusion, this study reveals MIR449A as a crucial direct target of the MECOM locus protein EVI1 involved in the pathogenesis of MECOM-rearranged leukaemias and unravels NOTCH1 and BCL2 as important novel targets of MIR449A. This EVI1-MIR449A-NOTCH1/BCL2 regulatory axis might open new possibilities for the development of therapeutic strategies in this poor prognostic leukaemia subgroup.},
keywords = {},
pubstate = {ppublish},
tppubtype = {article}
}
Taveirne, Sylvie; Filtjens, Jessica; Ammel, Els Van; Colvenaer, Veerle De; Kerre, Tessa; Taghon, Tom; Vandekerckhove, Bart; Plum, Jean; Held, Werner; Leclercq, Georges
Inhibitory receptors specific for MHC class I educate murine NK cells but not CD8αα intestinal intraepithelial T lymphocytes. Journal Article
In: Blood, vol. 118, pp. 339–347, 2011, ISSN: 1528-0020.
@article{Taveirne2011,
title = {Inhibitory receptors specific for MHC class I educate murine NK cells but not CD8αα intestinal intraepithelial T lymphocytes.},
author = {Sylvie Taveirne and Jessica Filtjens and Els Van Ammel and Veerle De Colvenaer and Tessa Kerre and Tom Taghon and Bart Vandekerckhove and Jean Plum and Werner Held and Georges Leclercq},
doi = {10.1182/blood-2011-01-331124},
issn = {1528-0020},
year = {2011},
date = {2011-07-01},
journal = {Blood},
volume = {118},
pages = {339--347},
abstract = {The engagement of inhibitory receptors specific for major histocompatibility complex class I (MHC-I) molecules educates natural killer (NK) cells, meaning the improvement of the response of activation receptors to subsequent stimulation. It is not known whether inhibitory MHC-I receptors educate only NK cells or whether they improve the responsiveness of all cell types, which express them. To address this issue, we analyzed the expression of inhibitory MHC-I receptors on intestinal intraepithelial lymphocytes (iIELs) and show that T-cell receptor (TCR)-αβ CD8αα iIELs express multiple inhibitory receptors specific for MHC-I molecules, including CD94/NKG2A, Ly49A, and Ly49G2. However, the presence of MHC-I ligand for these receptors did not improve the response of iIELs to activation via the TCR. The absence of iIEL education by MHC-I receptors was not related to a lack of inhibitory function of these receptors in iIELs and a failure of these receptors to couple to the TCR. Thus, unlike NK cells, iIELs do not undergo an MHC-I-guided education process. These data suggest that education is an NK cell-specific function of inhibitory MHC-I receptors.},
keywords = {},
pubstate = {ppublish},
tppubtype = {article}
}
Taveirne, Sylvie; Colvenaer, Veerle De; Broeck, Tina Van Den; Ammel, Els Van; Bennett, Clare L; Taghon, Tom; Vandekerckhove, Bart; Plum, Jean; Clausen, Björn E; Kaplan, Daniel H; Leclercq, Georges
Langerhans cells are not required for epidermal Vgamma3 T cell homeostasis and function. Journal Article
In: Journal of leukocyte biology, vol. 90, pp. 61–68, 2011, ISSN: 1938-3673.
@article{Taveirne2011a,
title = {Langerhans cells are not required for epidermal Vgamma3 T cell homeostasis and function.},
author = {Sylvie Taveirne and Veerle De Colvenaer and Tina Van Den Broeck and Els Van Ammel and Clare L Bennett and Tom Taghon and Bart Vandekerckhove and Jean Plum and Björn E Clausen and Daniel H Kaplan and Georges Leclercq},
doi = {10.1189/jlb.1010581},
issn = {1938-3673},
year = {2011},
date = {2011-07-01},
journal = {Journal of leukocyte biology},
volume = {90},
pages = {61--68},
abstract = {This study tested the hypothesis that Vγ3 TCR-bearing T cells are influenced by LCs. Vγ3 T cells and LCs are located in the epidermis of mice. Vγ3 T cells represent the main T cell population in the skin epithelium and play a crucial role in maintaining the skin integrity, whereas LCs are professional APCs. Although Vγ3 T cells and LCs form an interdigitating network in the epidermis, not much is known about their reciprocal influence and/or interdependence. We used two different LC-deficient mouse models, in which LCs are constitutively or inducibly depleted, to investigate the role of LCs in maturation, homeostasis, and function of Vγ3 T cells. We show that Vγ3 T cell numbers are unaltered by LC deficiency, and Vγ3 T cells isolated from LC-deficient mice are phenotypically and upon in vitro stimulation, functionally indistinguishable from Vγ3 T cells isolated from WT mice based on their cytotoxic potential and cytokine production. Additionally, in vivo skin-wounding experiments show no major difference in response of Vγ3 T cells to wounding in the absence or presence of LCs. These observations indicate that Vγ3 T cells develop and function independently of LCs.},
keywords = {},
pubstate = {ppublish},
tppubtype = {article}
}
Mavrakis, Konstantinos J; Meulen, Joni Van Der; Wolfe, Andrew L; Liu, Xiaoping; Mets, Evelien; Taghon, Tom; Khan, Aly A; Setty, Manu; Setti, Manu; Rondou, Pieter; Vandenberghe, Peter; Delabesse, Eric; Benoit, Yves; Socci, Nicholas B; Leslie, Christina S; Vlierberghe, Pieter Van; Speleman, Frank; Wendel, Hans-Guido
A cooperative microRNA-tumor suppressor gene network in acute T-cell lymphoblastic leukemia (T-ALL). Journal Article
In: Nature genetics, vol. 43, pp. 673–678, 2011, ISSN: 1546-1718.
@article{Mavrakis2011,
title = {A cooperative microRNA-tumor suppressor gene network in acute T-cell lymphoblastic leukemia (T-ALL).},
author = {Konstantinos J Mavrakis and Joni Van Der Meulen and Andrew L Wolfe and Xiaoping Liu and Evelien Mets and Tom Taghon and Aly A Khan and Manu Setty and Manu Setti and Pieter Rondou and Peter Vandenberghe and Eric Delabesse and Yves Benoit and Nicholas B Socci and Christina S Leslie and Pieter Van Vlierberghe and Frank Speleman and Hans-Guido Wendel},
doi = {10.1038/ng.858},
issn = {1546-1718},
year = {2011},
date = {2011-06-01},
journal = {Nature genetics},
volume = {43},
pages = {673--678},
abstract = {The importance of individual microRNAs (miRNAs) has been established in specific cancers. However, a comprehensive analysis of the contribution of miRNAs to the pathogenesis of any specific cancer is lacking. Here we show that in T-cell acute lymphoblastic leukemia (T-ALL), a small set of miRNAs is responsible for the cooperative suppression of several tumor suppressor genes. Cross-comparison of miRNA expression profiles in human T-ALL with the results of an unbiased miRNA library screen allowed us to identify five miRNAs (miR-19b, miR-20a, miR-26a, miR-92 and miR-223) that are capable of promoting T-ALL development in a mouse model and which account for the majority of miRNA expression in human T-ALL. Moreover, these miRNAs produce overlapping and cooperative effects on tumor suppressor genes implicated in the pathogenesis of T-ALL, including IKAROS (also known as IKZF1), PTEN, BIM, PHF6, NF1 and FBXW7. Thus, a comprehensive and unbiased analysis of miRNA action in T-ALL reveals a striking pattern of miRNA-tumor suppressor gene interactions in this cancer.},
keywords = {},
pubstate = {epublish},
tppubtype = {article}
}
Smedt, Magda De; Leclercq, Georges; Vandekerckhove, Bart; Kerre, Tessa; Taghon, Tom; Plum, Jean
In: Haematologica, vol. 96, pp. 646–654, 2011, ISSN: 1592-8721.
@article{DeSmedt2011,
title = {T-lymphoid differentiation potential measured in vitro is higher in CD34+CD38-/lo hematopoietic stem cells from umbilical cord blood than from bone marrow and is an intrinsic property of the cells.},
author = {Magda De Smedt and Georges Leclercq and Bart Vandekerckhove and Tessa Kerre and Tom Taghon and Jean Plum},
doi = {10.3324/haematol.2010.036343},
issn = {1592-8721},
year = {2011},
date = {2011-05-01},
journal = {Haematologica},
volume = {96},
pages = {646--654},
abstract = {Human bone marrow and umbilical cord blood are sources of allogeneic hematopoietic stem cells for transplantation, which is a life-saving treatment in a variety of diseases but is burdened by delayed T-cell reconstitution. Observational studies evaluating T-cell reconstitution in post-transplant recipients suggest that cord blood hematopoietic stem cells have a more effective capacity for T-cell reconstitution. This study focuses on the comparison of the capacity of cord blood and bone marrow hematopoietic stem cells to generate T cells in vitro. Hematopoietic stem cells were cultured in OP9-delta-like-1 and OP9-green fluorescent protein co-cultures to estimate T and myeloid generation capacity, respectively. Phenotypic markers of T-lineage or myeloid differentiation were measured by flow cytometry and used to analyze their kinetics as a function of culture time. Hematopoietic stem cells were labeled with carboxyfluorescein diacetate succinamidyl ester and analyzed after culture to track their phenotypic progression in consecutive generations. Mixed OP9-delta-like-1 co-cultures were done with either carboxyfluorescein diacetate succinamidyl ester-labeled bone marrow and unlabeled cord blood hematopoietic stem cells, or vice versa, to evaluate their mutual influence on T-lineage differentiation. The T-cell potential of hematopoietic stem cells was addressed quantitatively by limiting dilution analysis. Bulk cultures showed faster and more extensive T-cell differentiation by cord blood hematopoietic stem cells. Furthermore, the T-lymphoid differentiation capacity of cord blood and bone marrow hematopoietic stem cells can be discriminated very early based on the coordinated expression of CD34 and CD7. Mixing experiments with cord blood hematopoietic stem cells and bone marrow hematopoietic stem cells showed that these differences are cell intrinsic. Quantitative clonal analyses demonstrated that CD34(+)CD38(-/lo) hematopoietic stem cells from cord blood contained a two-fold higher T-lineage generation capacity than CD34(+)CD38(-/lo) bone marrow hematopoietic stem cells, whereas the myeloid differentiation was similar. Our data shows that cord blood hematopoietic stem cells have higher T-lymphoid differentiation potential than bone marrow hematopoietic stem cells and that this property is cell autonomous.},
keywords = {},
pubstate = {ppublish},
tppubtype = {article}
}
Klinakis, Apostolos; Lobry, Camille; Abdel-Wahab, Omar; Oh, Philmo; Haeno, Hiroshi; Buonamici, Silvia; van De Walle, Inge; Cathelin, Severine; Trimarchi, Thomas; Araldi, Elisa; Liu, Cynthia; Ibrahim, Sherif; Beran, Miroslav; Zavadil, Jiri; Efstratiadis, Argiris; Taghon, Tom; Michor, Franziska; Levine, Ross L; Aifantis, Iannis
A novel tumour-suppressor function for the Notch pathway in myeloid leukaemia. Journal Article
In: Nature, vol. 473, pp. 230–233, 2011, ISSN: 1476-4687.
@article{Klinakis2011,
title = {A novel tumour-suppressor function for the Notch pathway in myeloid leukaemia.},
author = {Apostolos Klinakis and Camille Lobry and Omar Abdel-Wahab and Philmo Oh and Hiroshi Haeno and Silvia Buonamici and Inge van De Walle and Severine Cathelin and Thomas Trimarchi and Elisa Araldi and Cynthia Liu and Sherif Ibrahim and Miroslav Beran and Jiri Zavadil and Argiris Efstratiadis and Tom Taghon and Franziska Michor and Ross L Levine and Iannis Aifantis},
doi = {10.1038/nature09999},
issn = {1476-4687},
year = {2011},
date = {2011-05-01},
journal = {Nature},
volume = {473},
pages = {230--233},
abstract = {Notch signalling is a central regulator of differentiation in a variety of organisms and tissue types. Its activity is controlled by the multi-subunit γ-secretase (γSE) complex. Although Notch signalling can play both oncogenic and tumour-suppressor roles in solid tumours, in the haematopoietic system it is exclusively oncogenic, notably in T-cell acute lymphoblastic leukaemia, a disease characterized by Notch1-activating mutations. Here we identify novel somatic-inactivating Notch pathway mutations in a fraction of patients with chronic myelomonocytic leukaemia (CMML). Inactivation of Notch signalling in mouse haematopoietic stem cells (HSCs) results in an aberrant accumulation of granulocyte/monocyte progenitors (GMPs), extramedullary haematopoieisis and the induction of CMML-like disease. Transcriptome analysis revealed that Notch signalling regulates an extensive myelomonocytic-specific gene signature, through the direct suppression of gene transcription by the Notch target Hes1. Our studies identify a novel role for Notch signalling during early haematopoietic stem cell differentiation and suggest that the Notch pathway can play both tumour-promoting and -suppressive roles within the same tissue.},
keywords = {},
pubstate = {ppublish},
tppubtype = {article}
}
de Walle, Inge Van; Smet, Greet De; Gärtner, Martina; Smedt, Magda De; Waegemans, Els; Vandekerckhove, Bart; Leclercq, Georges; Plum, Jean; Aster, Jon C; Bernstein, Irwin D; Guidos, Cynthia J; Kyewski, Bruno; Taghon, Tom
Jagged2 acts as a Delta-like Notch ligand during early hematopoietic cell fate decisions. Journal Article
In: Blood, vol. 117, pp. 4449–4459, 2011, ISSN: 1528-0020.
@article{VandeWalle2011,
title = {Jagged2 acts as a Delta-like Notch ligand during early hematopoietic cell fate decisions.},
author = {Inge Van de Walle and Greet De Smet and Martina Gärtner and Magda De Smedt and Els Waegemans and Bart Vandekerckhove and Georges Leclercq and Jean Plum and Jon C Aster and Irwin D Bernstein and Cynthia J Guidos and Bruno Kyewski and Tom Taghon},
doi = {10.1182/blood-2010-06-290049},
issn = {1528-0020},
year = {2011},
date = {2011-04-01},
journal = {Blood},
volume = {117},
pages = {4449--4459},
abstract = {Notch signaling critically mediates various hematopoietic lineage decisions and is induced in mammals by Notch ligands that are classified into 2 families, Delta-like (Delta-like-1, -3 and -4) and Jagged (Jagged1 and Jagged2), based on structural homology with both Drosophila ligands Delta and Serrate, respectively. Because the functional differences between mammalian Notch ligands were still unclear, we have investigated their influence on early human hematopoiesis and show that Jagged2 affects hematopoietic lineage decisions very similarly as Delta-like-1 and -4, but very different from Jagged1. OP9 coculture experiments revealed that Jagged2, like Delta-like ligands, induces T-lineage differentiation and inhibits B-cell and myeloid development. However, dose-dependent Notch activation studies, gene expression analysis, and promoter activation assays indicated that Jagged2 is a weaker Notch1-activator compared with the Delta-like ligands, revealing a Notch1 specific signal strength hierarchy for mammalian Notch ligands. Strikingly, Lunatic-Fringe- mediated glycosylation of Notch1 potentiated Notch signaling through Delta-like ligands and also Jagged2, in contrast to Jagged1. Thus, our results reveal a unique role for Jagged1 in preventing the induction of T-lineage differentiation in hematopoietic stem cells and show an unexpected functional similarity between Jagged2 and the Delta-like ligands.},
keywords = {},
pubstate = {ppublish},
tppubtype = {article}
}
Vandekerckhove, Bart; Vanhee, Stijn; Coppernolle, Stefanie Van; Snauwaert, Sylvia; Velghe, Imke; Taghon, Tom; Leclercq, Georges; Kerre, Tessa; Plum, Jean
In vitro generation of immune cells from pluripotent stem cells. Journal Article
In: Frontiers in bioscience (Landmark edition), vol. 16, pp. 1488–1504, 2011, ISSN: 2768-6698.
@article{Vandekerckhove2011,
title = {In vitro generation of immune cells from pluripotent stem cells.},
author = {Bart Vandekerckhove and Stijn Vanhee and Stefanie Van Coppernolle and Sylvia Snauwaert and Imke Velghe and Tom Taghon and Georges Leclercq and Tessa Kerre and Jean Plum},
doi = {10.2741/3800},
issn = {2768-6698},
year = {2011},
date = {2011-01-01},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {16},
pages = {1488--1504},
abstract = {Stem cell transplant recipients and acquired or inherited immune-deficiency patients could benefit from the infusion of B, T and/or NK cells. These lymphoid cells can be generated in vitro from bone marrow derived CD34+CD45+ hematopoietic stem cells (HSC). The number of cells that can be obtained in this way is limited especially in the adult. An alternative source may therefore constitute human pluripotent stem cells (PSC) such as embryonic (hESC) or induced pluripotent stem cells (hiPSC). Here, we focus on present knowledge on the generation of lymphoid cells from hESC. The two main obstacles for the generation of clinically relevant immune cells are the failure to generate from hESC long-term repopulating HSC which could be kept in culture for prolonged time; and insufficient knowledge of the selection process which generates mature T cells from CD4 CD8 double positive (DP) precursors in vitro.},
keywords = {},
pubstate = {epublish},
tppubtype = {article}
}
2010
Colvenaer, Veerle De; Taveirne, Sylvie; Hamann, Jörg; de Bruin, Alex M; Smedt, Magda De; Taghon, Tom; Vandekerckhove, Bart; Plum, Jean; van Lier, René; Leclercq, Georges
Continuous CD27 triggering in vivo strongly reduces NK cell numbers. Journal Article
In: European journal of immunology, vol. 40, pp. 1107–1117, 2010, ISSN: 1521-4141.
@article{DeColvenaer2010,
title = {Continuous CD27 triggering in vivo strongly reduces NK cell numbers.},
author = {Veerle De Colvenaer and Sylvie Taveirne and Jörg Hamann and Alex M de Bruin and Magda De Smedt and Tom Taghon and Bart Vandekerckhove and Jean Plum and René van Lier and Georges Leclercq},
doi = {10.1002/eji.200939251},
issn = {1521-4141},
year = {2010},
date = {2010-04-01},
journal = {European journal of immunology},
volume = {40},
pages = {1107--1117},
abstract = {NK cells are important mediators of the early defense. In mice, immature and mature NK (mNK) cells constitutively express the TNF receptor family member CD27; however, mNK cells eventually lose CD27 expression and become resting NK cells. Interaction of CD27 with its ligand, CD70, enhances proliferation and effector functions of NK cells. We used mice that constitutively express CD70 on B cells (CD70-Tg) to study the in vivo effects of continuous triggering of CD27 on NK cells. Continuous CD70-CD27 interaction resulted in strongly down-modulated CD27 expression on NK cells and gradually reduced absolute NK cell numbers. This reduction was most prominent in the mNK cell subpopulation and was at least partially due to increased apoptosis. Residual NK cells showed lower expression of activating Ly49 receptors and normal (liver) or decreased (spleen) IFN-gamma production. Nevertheless, NK cells from CD70-Tg mice displayed higher YAC-1 killing capacities. CD70-Tg NK cells exhibited up-regulated expression of NKG2D, which is in accordance with the increased YAC-1 lysis, as this is mainly NKG2D-dependent. Taken together, this study is the first to demonstrate that continuous CD70 triggering of CD27 on NK cells in vivo results in a severe reduction of NK cells. On a single cell basis, however, residual NK cells display enhanced cytotoxicity.},
keywords = {},
pubstate = {ppublish},
tppubtype = {article}
}