Publications

@article{Liang2023b,

title = {Circulating IRF8-expressing CD123⁺CD127⁺ lymphoid progenitors: key players in human hematopoiesis.},

author = {Kai Ling Liang and Elisa Laurenti and Tom Taghon},

doi = {10.1016/j.it.2023.07.004},

issn = {1471-4981},

year  = {2023},

date = {2023-08-01},

journal = {Trends in immunology},

abstract = {Lymphopoiesis is the process in which B and T cells, and innate lymphoid cells (ILCs) develop from hematopoietic progenitors that exhibit early lymphoid priming. The branching points where lymphoid-primed human progenitors are further specified to B/T/ILC differentiation trajectories remain unclear. Here, we discuss the emerging role of interferon regulatory factor (IRF)8 as a key factor to bridge human lymphoid and dendritic cell (DC) differentiation, and the current evidence for the existence of circulating and tissue-resident CD123⁺CD127⁺ lymphoid progenitors. We propose a model whereby DC/B/T/ILC lineage programs in circulating CD123⁺CD127⁺ lymphoid progenitors are expressed in balance. Upon tissue seeding, the tissue microenvironment tilts this molecular balance towards a specific lineage, thereby determining in vivo lineage fates. Finally, we discuss the translational implication of these lymphoid precursors.},

keywords = {},

pubstate = {aheadofprint},

tppubtype = {article}

}

@article{Billiet2023,

title = {Single-cell profiling identifies a novel human polyclonal unconventional T cell lineage.},

author = {Lore Billiet and Laurenz De Cock and Guillem Sanchez Sanchez and Rupert L. Mayer and Glenn Goetgeluk and Stijn De Munter and Melissa Pille and Joline Ingels and Hanne Jansen and Karin Weening and Eva Pascal and Killian Raes and Sarah Bonte and Tessa Kerre and Niels Vandamme and Ruth Seurinck and Jana Roels and Marieke Lavaert and Filip Van Nieuwerburgh and Georges Leclercq and Tom Taghon and Francis Impens and Björn Menten and David Vermijlen and Bart Vandekerckhove},

doi = {10.1084/jem.20220942},

issn = {1540-9538},

year  = {2023},

date = {2023-06-01},

journal = {The Journal of experimental medicine},

volume = {220},

issue = {6},

abstract = {In the human thymus, a CD10+ PD-1+ TCRαβ+ differentiation pathway diverges from the conventional single positive T cell lineages at the early double-positive stage. Here, we identify the progeny of this unconventional lineage in antigen-inexperienced blood. These unconventional T cells (UTCs) in thymus and blood share a transcriptomic profile, characterized by hallmark transcription factors (i.e., ZNF683 and IKZF2), and a polyclonal TCR repertoire with autoreactive features, exhibiting a bias toward early TCRα chain rearrangements. Single-cell RNA sequencing confirms a common developmental trajectory between the thymic and blood UTCs and clearly delineates this unconventional lineage in blood. Besides MME+ recent thymic emigrants, effector-like clusters are identified in this heterogeneous lineage. Expression of Helios and KIR and a decreased CD8β expression are characteristics of this lineage. This UTC lineage could be identified in adult blood and intestinal tissues. In summary, our data provide a comprehensive characterization of the polyclonal unconventional lineage in antigen-inexperienced blood and identify the adult progeny.},

keywords = {},

pubstate = {ppublish},

tppubtype = {article}

}

@article{Guo2023,

title = {RNA helicase DHX15 exemplifies a unique dependency in acute leukemia.},

author = {Hao Guo and Jin Xu and Peiqi Xing and Qilong Li and Donghai Wang and Chao Tang and Bruno Palhais and Juliette Roels and Jiaxu Liu and Sa Pan and Jinyan Huang and Zhaoqi Liu and Ping Zhu and Tom Taghon and Guoliang Qing and Pieter Van Vlierberghe and Hudan Liu},

doi = {10.3324/haematol.2022.282066},

issn = {1592-8721},

year  = {2023},

date = {2023-03-01},

journal = {Haematologica},

abstract = {RNA-binding proteins (RBPs) have emerged as essential regulators to control gene expression and modulate multiple cancer traits. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy derived from transformation of T-cell progenitors that normally undergo discrete steps of differentiation in the thymus. Yet implications of essential RBPs during T-cell neoplastic transformation remain largely unclear. Systematic evaluation of RBPs identifies RNA helicase DHX15, which facilitates the disassembly of spliceosome and release of lariat introns, as a T-ALL dependency factor. Functional analysis using multiple murine T-ALL models demonstrates the essential importance of DHX15 in tumor cell survival and leukemogenesis. Moreover, single-cell transcriptomics reveals that DHX15 depletion in T-cell progenitors hinders burst proliferation during CD4-CD8-(DN)-to-CD4+CD8+(DP) transition. Mechanistically, abrogation of DHX15 perturbs RNA splicing and leads to diminished levels of SLC7A6 and SLC38A5 transcripts due to intron retention, thereby suppressing glutamine import and mTORC1 activity. We further propose a DHX15 signature modulator drug ciclopirox and demonstrate prominent anti-T-ALL efficacy. Collectively, we here highlight the functional contribution of DHX15 to leukemogenesis through regulation of established oncogenic pathways. These findings also suggest a promising therapeutic approach that splicing perturbation by targeting spliceosome disassembly may achieve considerable anti-tumor efficacy.},

keywords = {},

pubstate = {aheadofprint},

tppubtype = {article}

}

@article{Liang2023,

title = {Intrathymic dendritic cell-biased precursors promote human T cell lineage specification through IRF8-driven transmembrane TNF.},

author = {Kai Ling Liang and Juliette Roels and Marieke Lavaert and Tom Putteman and Lena Boehme and Laurentijn Tilleman and Imke Velghe and Valentina Pegoretti and Inge Van de Walle and Stephanie Sontag and Jolien Vandewalle and Bart Vandekerckhove and Georges Leclercq and Pieter Van Vlierberghe and Claude Libert and Filip Van Nieuwerburgh and Roman Fischer and Roland E Kontermann and Klaus Pfizenmaier and Gina Doody and Martin Zenke and Tom Taghon},

doi = {10.1038/s41590-022-01417-6},

issn = {1529-2916},

year  = {2023},

date = {2023-01-01},

journal = {Nature immunology},

abstract = {The cross-talk between thymocytes and thymic stromal cells is fundamental for T cell development. In humans, intrathymic development of dendritic cells (DCs) is evident but its physiological significance is unknown. Here we showed that DC-biased precursors depended on the expression of the transcription factor IRF8 to express the membrane-bound precursor form of the cytokine TNF (tmTNF) to promote differentiation of thymus seeding hematopoietic progenitors into T-lineage specified precursors through activation of the TNF receptor (TNFR)-2 instead of TNFR1. In vitro recapitulation of TNFR2 signaling by providing low-density tmTNF or a selective TNFR2 agonist enhanced the generation of human T cell precursors. Our study shows that, in addition to mediating thymocyte selection and maturation, DCs function as hematopoietic stromal support for the early stages of human T cell development and provide proof of concept that selective targeting of TNFR2 can enhance the in vitro generation of T cell precursors for clinical application.},

keywords = {},

pubstate = {aheadofprint},

tppubtype = {article}

}

@article{Provez2023,

title = {Pre-Clinical Evaluation of the Hypomethylating Agent Decitabine for the Treatment of T-Cell Lymphoblastic Lymphoma.},

author = {Lien Provez and Tom Putteman and Mattias Landfors and Juliette Roels and Lindy Reunes and Sara T'Sas and Wouter Van Loocke and Béatrice Lintermans and Stien De Coninck and Morgan Thenoz and Wouter Sleeckx and Natalia Maćkowska-Maślak and Tom Taghon and Marc R Mansour and Nadine Farah and Koen Norga and Peter Vandenberghe and Rishi S Kotecha and Steven Goossens and Sofie Degerman and Renate De Smedt and Pieter Van Vlierberghe},

doi = {10.3390/cancers15030647},

issn = {2072-6694},

year  = {2023},

date = {2023-01-01},

journal = {Cancers},

volume = {15},

abstract = {T-cell lymphoblastic lymphoma (T-LBL) is a rare and aggressive lymphatic cancer, often diagnosed at a young age. Patients are treated with intensive chemotherapy, potentially followed by a hematopoietic stem cell transplantation. Although prognosis of T-LBL has improved with intensified treatment protocols, they are associated with side effects and 10-20% of patients still die from relapsed or refractory disease. Given this, the search toward less toxic anti-lymphoma therapies is ongoing. Here, we targeted the recently described DNA hypermethylated profile in T-LBL with the DNA hypomethylating agent decitabine. We evaluated the anti-lymphoma properties and downstream effects of decitabine, using patient derived xenograft (PDX) models. Decitabine treatment resulted in prolonged lymphoma-free survival in all T-LBL PDX models, which was associated with downregulation of the oncogenic MYC pathway. However, some PDX models showed more benefit of decitabine treatment compared to others. In more sensitive models, differentially methylated CpG regions resulted in more differentially expressed genes in open chromatin regions. This resulted in stronger downregulation of cell cycle genes and upregulation of immune response activating transcripts. Finally, we suggest a gene signature for high decitabine sensitivity in T-LBL. Altogether, we here delivered pre-clinical proof of the potential use of decitabine as a new therapeutic agent in T-LBL.},

keywords = {},

pubstate = {epublish},

tppubtype = {article}

}

@article{VandeWalle2023,

title = {Identification and Purification of Human T Cell Precursors.},

author = {Inge Van de Walle and Nina Lambrechts and Anaïs Derveeuw and Marieke Lavaert and Juliette Roels and Tom Taghon},

doi = {10.1007/978-1-0716-2740-2_20},

issn = {1940-6029},

year  = {2023},

date = {2023-01-01},

journal = {Methods in molecular biology (Clifton, N.J.)},

volume = {2580},

pages = {315--333},

abstract = {During their development, human T cells undergo similar genomic changes and pass through the same developmental checkpoints as developing thymocytes in the mouse. The difference between both species, however, is that some of these developmental stages are characterized by different phenotypic markers, and as a result, evidence emerges that the molecular regulation of human T cell development subtly differs from the mouse (Taghon et al., Curr Top Microbiol Immunol 360:75-97, 2021; Haddad et al., Immunity 24:217-230, 2006; Hao et al., Blood 111:1318-1326, 2008; Taghon and Rothenberg, Semin Immunopathol 30:383-398, 2008). In this chapter, we describe in detail how the different stages of human T cell development can be characterized and isolated using specific surface markers.},

keywords = {},

pubstate = {ppublish},

tppubtype = {article}

}

@article{Lambrechts2023,

title = {In Vitro Model Systems to Study Human T Cell Development.},

author = {Nina Lambrechts and Kai Ling Liang and Imke Velghe and Steven Strubbe and Anne-Catherine Dolens and Tom Taghon},

doi = {10.1007/978-1-0716-2740-2_21},

issn = {1940-6029},

year  = {2023},

date = {2023-01-01},

journal = {Methods in molecular biology (Clifton, N.J.)},

volume = {2580},

pages = {335--354},

abstract = {Not only is human T cell development characterized by unique changes in surface marker expression, but it also requires specific growth factors and conditions to mimic and study T cell development in vitro. In this chapter, we provide an overview of the specific aspects that need attention when performing T cell differentiation cultures with human hematopoietic and T cell progenitors.},

keywords = {},

pubstate = {ppublish},

tppubtype = {article}

}

@article{Pille2023,

title = {The Wiskott–Aldrich syndrome protein is required for positive selection during T-cell lineage differentiation},

author = {Melissa Pille and John Avila and Guillem Sanchez Sanchez and Guillem Sanchez Sanchez and Guillem Sanchez Sanchez and Guillem Sanchez Sanchez and Glenn Goetgeluk and Glenn Goetgeluk and Stijn De Munter and Stijn De Munter and Hanne Jansen and Lore Billiet and Karin Weening and Haipeng Xue and Sarah Bonte and Sarah Bonte and Joline Ingels and Joline Ingels and Laurenz De Cock and Laurenz De Cock and Eva Pascal and Eva Pascal and Lucas Deseins and Lucas Deseins and Tessa Kerre and Tessa Kerre and Tom Taghon and Tom Taghon and Georges Leclercq and Georges Leclercq and David Vermijlen and David Vermijlen and David Vermijlen and David Vermijlen and Brian Davis and Bart Vandekerckhove and Bart Vandekerckhove},

url = {https://www.frontiersin.org/articles/10.3389/fimmu.2023.1188099/full},

doi = {10.3389/fimmu.2023.1188099},

issn = {1664-3224},

year  = {2023},

date = {2023-01-01},

journal = {Frontiers in Immunology},

volume = {14},

publisher = {Frontiers Media S.A.},

abstract = {The Wiskott–Aldrich syndrome (WAS) is an X-linked primary immune deficiency caused by a mutation in the WAS gene. This leads to altered or absent WAS protein (WASp) expression and function resulting in thrombocytopenia, eczema, recurrent infections, and autoimmunity. In T cells, WASp is required for immune synapse formation. Patients with WAS show reduced numbers of peripheral blood T lymphocytes and an altered T-cell receptor repertoire. In vitro, their peripheral T cells show decreased proliferation and cytokine production upon aCD3/aCD28 stimulation. It is unclear whether these T-cell defects are acquired during peripheral activation or are, in part, generated during thymic development. Here, we assessed the role of WASp during T-cell differentiation using artificial thymic organoid cultures and in the thymus of humanized mice. Although CRISPR/Cas9 WAS knockout hematopoietic stem and progenitor cells (HSPCs) rearranged the T-cell receptor and differentiated to T-cell receptor (TCR)+ CD4+ CD8+ double-positive (DP) cells similar to wild-type HSPCs, a partial defect in the generation of CD8 single-positive (SP) cells was observed, suggesting that WASp is involved in their positive selection. TCR repertoire analysis of the DP and CD8+ SP population, however, showed a polyclonal repertoire with no bias toward autoreactivity. To our knowledge, this is the first study of the role of WASp in human T-cell differentiation and on TCR repertoire generation.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{DrobnaSledzinska2022,

title = {Multiomics to investigate the mechanisms contributing to repression of PTPRC and SOCS2 in pediatric T-ALL: Focus on miR-363-3p and promoter methylation.},

author = {Monika Drobna-Śledzińska and Natalia Maćkowska-Maślak and Roman Jaksik and Maria Kosmalska and Bronisława Szarzyńska and Monika Lejman and Łukasz Sędek and Tomasz Szczepański and Tom Taghon and Pieter Van Vlierberghe and Michał Witt and Małgorzata Dawidowska},

doi = {10.1002/gcc.23085},

issn = {1098-2264},

year  = {2022},

date = {2022-07-01},

journal = {Genes, chromosomes & cancer},

abstract = {T-cell acute lymphoblastic leukemia (T-ALL) is a heterogeneous and aggressive malignancy arising from T-cell precursors. MiRNAs are implicated in negative regulation of gene expression and when aberrantly expressed contribute to various cancer types, including T-ALL. Previously we demonstrated the oncogenic potential of miR-363-3p overexpression in a subgroup of T-ALL patients. Here, using combined proteomic and transcriptomic approaches, we show that miR-363-3p enhances cell growth of T-ALL in vitro via inhibition of PTPRC and SOCS2, which are implicated in repression of the JAK-STAT pathway. We propose that overexpression of miR-363-3p is a novel mechanism potentially contributing to overactivation of JAK-STAT pathway. Additionally, by combining the transcriptomic and methylation data of T-ALL patients, we show that promoter methylation may also contribute to downregulation of SOCS2 expression and thus potentially to JAK-STAT activation. In conclusion, we highlight aberrant miRNA expression and aberrant promoter methylation as mechanisms, alternative to mutations of JAK-STAT-related genes, which might lead to the upregulation of JAK-dependent signaling in T-ALL.},

keywords = {},

pubstate = {aheadofprint},

tppubtype = {article}

}

@article{Ingels2022,

title = {Small-scale manufacturing of neoantigen-encoding messenger RNA for early-phase clinical trials.},

author = {Joline Ingels and Laurenz De Cock and Rupert L Mayer and Pam Devreker and Karin Weening and Kelly Heyns and Nele Lootens and Saskia De Smet and Marieke Brusseel and Stijn De Munter and Melissa Pille and Lore Billiet and Glenn Goetgeluk and Sarah Bonte and Hanne Jansen and Sandra Van Lint and Georges Leclercq and Tom Taghon and Björn Menten and Karim Vermaelen and Francis Impens and Bart Vandekerckhove},

doi = {10.1016/j.jcyt.2021.08.005},

issn = {1477-2566},

year  = {2022},

date = {2022-02-01},

journal = {Cytotherapy},

volume = {24},

pages = {213--222},

abstract = {Messenger RNA (mRNA) has become a promising tool in therapeutic cancer vaccine strategies. Owing to its flexible design and rapid production, mRNA is an attractive antigen delivery format for cancer vaccines targeting mutated peptides expressed in a tumor-the so-called neoantigens. These neoantigens are rarely shared between patients, and inclusion of these antigens in a vaccine requires the production of individual batches of patient-tailored mRNA. The authors have developed MIDRIX , a personalized mRNA-loaded dendritic cell vaccine targeting tumor neoantigens, which is currently being evaluated in a phase 1 clinical study in lung cancer patients. To facilitate this study, the authors set up a Good Manufacturing Practice (GMP)-compliant production process for the manufacture of small batches of personalized neoantigen-encoding mRNA. In this article, the authors describe the complete mRNA production process and the extensive quality assessment to which the mRNA is subjected. Validation runs have shown that the process delivers mRNA of reproducible, high quality. This process is now successfully applied for the production of neoantigen-encoding mRNA for the clinical evaluation of MIDRIX . To the authors' knowledge, this is the first time that a GMP-based production process of patient-tailored neoantigen mRNA has been described.},

keywords = {},

pubstate = {ppublish},

tppubtype = {article}

}

@article{Wahlen2022,

title = {The transcription factor RUNX2 drives the generation of human NK cells and promotes tissue residency.},

author = {Sigrid Wahlen and Filip Matthijssens and Wouter Van Loocke and Sylvie Taveirne and Laura Kiekens and Eva Persyn and Els Van Ammel and Zenzi De Vos and Stijn De Munter and Patrick Matthys and Filip Van Nieuwerburgh and Tom Taghon and Bart Vandekerckhove and Pieter Van Vlierberghe and Georges Leclercq},

doi = {10.7554/eLife.80320},

issn = {2050-084X},

year  = {2022},

date = {2022-01-01},

journal = {eLife},

volume = {11},

abstract = {Natural killer (NK) cells are innate lymphocytes that eliminate virus-infected and cancer cells by cytotoxicity and cytokine secretion. In addition to circulating NK cells, distinct tissue-resident NK subsets have been identified in various organs. Although transcription factors regulating NK cell development and function have been extensively studied in mice, the role of RUNX2 in these processes has not been investigated, neither in mice nor in human. Here, by manipulating RUNX2 expression with either knockdown or overexpression in human haematopoietic stem cell-based NK cell differentiation cultures, combined with transcriptomic and ChIP-sequencing analyses, we established that RUNX2 drives the generation of NK cells, possibly through induction of IL-2Rβ expression in NK progenitor cells. Importantly, RUNX2 promotes tissue residency in human NK cells. Our findings have the potential to improve existing NK cell-based cancer therapies and can impact research fields beyond NK cell biology, since tissue-resident subsets have also been described in other lymphocyte subpopulations.},

keywords = {},

pubstate = {epublish},

tppubtype = {article}

}

@article{Kiekens2022,

title = {T-BET drives the conversion of human type 3 innate lymphoid cells into functional NK cells.},

author = {Laura Kiekens and Sigrid Wahlen and Eva Persyn and Zenzi De Vos and Tom Taghon and Bart Vandekerckhove and Georges Leclercq},

doi = {10.3389/fimmu.2022.975778},

issn = {1664-3224},

year  = {2022},

date = {2022-01-01},

journal = {Frontiers in immunology},

volume = {13},

pages = {975778},

abstract = {Type 3 innate lymphoid cells (ILC3s) are characterized by RORγt expression and they produce IL-22 upon activation. ILC3s play a role in maintenance of barrier integrity in the intestine. Under inflammatory conditions, the ILC composition of the mucosal tissues is altered due to a high degree of plasticity. It has been extensively demonstrated that both murine and human ILC3s convert into ILC1s to mediate appropriate immune responses. However, plasticity between human ILC3s and NK cells is less well documented. As T-BET and EOMES are key transcription factors in NK cell differentiation, we investigated whether ectopic T-BET or EOMES expression converts human ILC3s into NK cells. ILC3s with ectopic T-BET and EOMES expression downregulate RORγt expression, while T-BET-overexpressing ILC3s additionally upregulate EOMES expression. High E ctopic T-BET expression in ILC3s results in transdifferentiation towards CD94 NK cells, whereas ectopic EOMES overexpression results in dedifferentiation of ILC3s into CD94-CD117 cells but is ineffective in NK cell generation. Dedifferentiating ILC3s from both T-BET and EOMES overexpression cultures upregulate NK cell receptors, perforin and granzyme B. Finally, IL-22 secretion is completely blocked in transdifferentiating ILC3s with both T-BET and EOMES ectopic expression, whereas only T-BET overexpression increases IFN-γ secretion and cytotoxicity. Altogether, these findings demonstrate that human ILC3s can convert into functional NK cells, wherein T-BET, and not EOMES, is the main driver.},

keywords = {},

pubstate = {epublish},

tppubtype = {article}

}

@article{Roels2022,

title = {Transcriptional dynamics and epigenetic regulation of E and ID protein encoding genes during human T cell development.},

author = {Juliette Roels and Jolien Van Hulle and Marieke Lavaert and Anna Kuchmiy and Steven Strubbe and Tom Putteman and Bart Vandekerckhove and Georges Leclercq and Filip Van Nieuwerburgh and Lena Boehme and Tom Taghon},

doi = {10.3389/fimmu.2022.960918},

issn = {1664-3224},

year  = {2022},

date = {2022-01-01},

journal = {Frontiers in immunology},

volume = {13},

pages = {960918},

abstract = {T cells are generated from hematopoietic stem cells through a highly organized developmental process, in which stage-specific molecular events drive maturation towards αβ and γδ T cells. Although many of the mechanisms that control αβ- and γδ-lineage differentiation are shared between human and mouse, important differences have also been observed. Here, we studied the regulatory dynamics of the E and ID protein encoding genes during pediatric human T cell development by evaluating changes in chromatin accessibility, histone modifications and bulk and single cell gene expression. We profiled patterns of ID/E protein activity and identified up- and downstream regulators and targets, respectively. In addition, we compared transcription of E and ID protein encoding genes in human versus mouse to predict both shared and unique activities in these species, and in prenatal versus pediatric human T cell differentiation to identify regulatory changes during development. This analysis showed a putative involvement of TCF3/E2A in the development of γδ T cells. In contrast, in αβ T cell precursors a pivotal pre-TCR-driven population with high ID gene expression and low predicted E protein activity was identified. Finally, in prenatal but not postnatal thymocytes, high HEB/TCF12 levels were found to counteract high ID levels to sustain thymic development. In summary, we uncovered novel insights in the regulation of E and ID proteins on a cross-species and cross-developmental level.},

keywords = {},

pubstate = {epublish},

tppubtype = {article}

}

@article{Persyn2022,

title = {TXNIP Promotes Human NK Cell Development but Is Dispensable for NK Cell Functionality.},

author = {Eva Persyn and Sigrid Wahlen and Laura Kiekens and Sylvie Taveirne and Wouter Van Loocke and Els Van Ammel and Filip Van Nieuwerburgh and Tom Taghon and Bart Vandekerckhove and Pieter Van Vlierberghe and Georges Leclercq},

doi = {10.3390/ijms231911345},

issn = {1422-0067},

year  = {2022},

date = {2022-01-01},

journal = {International journal of molecular sciences},

volume = {23},

abstract = {The ability of natural killer (NK) cells to kill tumor cells without prior sensitization makes them a rising player in immunotherapy. Increased understanding of the development and functioning of NK cells will improve their clinical utilization. As opposed to murine NK cell development, human NK cell development is still less understood. Here, we studied the role of thioredoxin-interacting protein (TXNIP) in human NK cell differentiation by stable TXNIP knockdown or overexpression in cord blood hematopoietic stem cells, followed by in vitro NK cell differentiation. TXNIP overexpression only had marginal effects, indicating that endogenous TXNIP levels are sufficient in this process. TXNIP knockdown, however, reduced proliferation of early differentiation stages and greatly decreased NK cell numbers. Transcriptome analysis and experimental confirmation showed that reduced protein synthesis upon TXNIP knockdown likely caused this low proliferation. Contrary to its profound effects on the early differentiation stages, TXNIP knockdown led to limited alterations in NK cell phenotype, and it had no effect on NK cell cytotoxicity or cytokine production. Thus, TXNIP promotes human NK cell differentiation by affecting protein synthesis and proliferation of early NK cell differentiation stages, but it is redundant for functional NK cell maturation.},

keywords = {},

pubstate = {epublish},

tppubtype = {article}

}

@article{Boehme2022,

title = {Development of γδ T cells in the thymus – A human perspective},

author = {Lena Boehme and Juliette Roels and Tom Taghon},

doi = {10.1016/j.smim.2022.101662},

issn = {1044-5323},

year  = {2022},

date = {2022-01-01},

volume = {61-64},

pages = {101662},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Persyn2022b,

title = {IRF2 is required for development and functional maturation of human NK cells.},

author = {Eva Persyn and Sigrid Wahlen and Laura Kiekens and Wouter Van Loocke and Hannah Siwe and Els Van Ammel and Zenzi De Vos and Filip Van Nieuwerburgh and Patrick Matthys and Tom Taghon and Bart Vandekerckhove and Pieter Van Vlierberghe and Georges Leclercq},

doi = {10.3389/fimmu.2022.1038821},

issn = {1664-3224},

year  = {2022},

date = {2022-01-01},

journal = {Frontiers in immunology},

volume = {13},

pages = {1038821},

abstract = {Natural killer (NK) cells are cytotoxic and cytokine-producing lymphocytes that play an important role in the first line of defense against malignant or virus-infected cells. A better understanding of the transcriptional regulation of human NK cell differentiation is crucial to improve the efficacy of NK cell-mediated immunotherapy for cancer treatment. Here, we studied the role of the transcription factor interferon regulatory factor (IRF) 2 in human NK cell differentiation by stable knockdown or overexpression in cord blood hematopoietic stem cells and investigated its effect on development and function of the NK cell progeny. IRF2 overexpression had limited effects in these processes, indicating that endogenous IRF2 expression levels are sufficient. However, IRF2 knockdown greatly reduced the cell numbers of all early differentiation stages, resulting in decimated NK cell numbers. This was not caused by increased apoptosis, but by decreased proliferation. Expression of IRF2 is also required for functional maturation of NK cells, as the remaining NK cells after silencing of IRF2 had a less mature phenotype and showed decreased cytotoxic potential, as well as a greatly reduced cytokine secretion. Thus, IRF2 plays an important role during development and functional maturation of human NK cells.},

keywords = {},

pubstate = {epublish},

tppubtype = {article}

}

@article{Strubbe2021,

title = {Modeling of human T cell development in vitro as a read-out for hematopoietic stem cell multipotency.},

author = {Steven Strubbe and Tom Taghon},

doi = {10.1042/BST20210144},

issn = {1470-8752},

year  = {2021},

date = {2021-11-01},

journal = {Biochemical Society transactions},

volume = {49},

pages = {2113--2122},

abstract = {Hematopoietic stem cells (HSCs) reside in distinct sites throughout fetal and adult life and give rise to all cells of the hematopoietic system. Because of their multipotency, HSCs are capable of curing a wide variety of blood disorders through hematopoietic stem cell transplantation (HSCT). However, due to HSC heterogeneity, site-specific ontogeny and current limitations in generating and expanding HSCs in vitro, their broad use in clinical practice remains challenging. To assess HSC multipotency, evaluation of their capacity to generate T lymphocytes has been regarded as a valid read-out. Several in vitro models of T cell development have been established which are able to induce T-lineage differentiation from different hematopoietic precursors, although with variable efficiency. Here, we review the potential of human HSCs from various sources to generate T-lineage cells using these different models in order to address the use of both HSCs and T cell precursors in the clinic.},

keywords = {},

pubstate = {ppublish},

tppubtype = {article}

}

@article{Lorenzi2021a,

title = {The RNA Atlas expands the catalog of human non-coding RNAs.},

author = {Lucia Lorenzi and Hua-Sheng Chiu and Francisco Avila Cobos and Stephen Gross and Pieter-Jan Volders and Robrecht Cannoodt and Justine Nuytens and Katrien Vanderheyden and Jasper Anckaert and Steve Lefever and Aidan P Tay and Eric J de Bony and Wim Trypsteen and Fien Gysens and Marieke Vromman and Tine Goovaerts and Thomas Birkballe Hansen and Scott Kuersten and Nele Nijs and Tom Taghon and Karim Vermaelen and Ken R Bracke and Yvan Saeys and Tim De Meyer and Nandan P Deshpande and Govardhan Anande and Ting-Wen Chen and Marc R Wilkins and Ashwin Unnikrishnan and Katleen De Preter and Jørgen Kjems and Jan Koster and Gary P Schroth and Jo Vandesompele and Pavel Sumazin and Pieter Mestdagh},

doi = {10.1038/s41587-021-00936-1},

issn = {1546-1696},

year  = {2021},

date = {2021-11-01},

journal = {Nature biotechnology},

volume = {39},

pages = {1453--1465},

abstract = {Existing compendia of non-coding RNA (ncRNA) are incomplete, in part because they are derived almost exclusively from small and polyadenylated RNAs. Here we present a more comprehensive atlas of the human transcriptome, which includes small and polyA RNA as well as total RNA from 300 human tissues and cell lines. We report thousands of previously uncharacterized RNAs, increasing the number of documented ncRNAs by approximately 8%. To infer functional regulation by known and newly characterized ncRNAs, we exploited pre-mRNA abundance estimates from total RNA sequencing, revealing 316 microRNAs and 3,310 long non-coding RNAs with multiple lines of evidence for roles in regulating protein-coding genes and pathways. Our study both refines and expands the current catalog of human ncRNAs and their regulatory interactions. All data, analyses and results are available for download and interrogation in the R2 web portal, serving as a basis for future exploration of RNA biology and function.},

keywords = {},

pubstate = {ppublish},

tppubtype = {article}

}

@article{Moirangthem2021,

title = {A DL-4- and TNFα-based culture system to generate high numbers of nonmodified or genetically modified immunotherapeutic human T-lymphoid progenitors.},

author = {Ranjita Devi Moirangthem and Kuiying Ma and Sabrina Lizot and Anne Cordesse and Juliette Olivré and Corinne de Chappedelaine and Akshay Joshi and Agata Cieslak and John Tchen and Nicolas Cagnard and Vahid Asnafi and Antonio Rausell and Laura Simons and Julien Zuber and Tom Taghon and Frank J T Staal and Françoise Pflumio and Emmanuelle Six and Marina Cavazzana and Chantal Lagresle-Peyrou and Tayebeh Soheili and Isabelle André},

doi = {10.1038/s41423-021-00706-8},

issn = {2042-0226},

year  = {2021},

date = {2021-07-01},

journal = {Cellular & molecular immunology},

volume = {18},

pages = {1662--1676},

abstract = {Several obstacles to the production, expansion and genetic modification of immunotherapeutic T cells in vitro have restricted the widespread use of T-cell immunotherapy. In the context of HSCT, delayed naïve T-cell recovery contributes to poor outcomes. A novel approach to overcome the major limitations of both T-cell immunotherapy and HSCT would be to transplant human T-lymphoid progenitors (HTLPs), allowing reconstitution of a fully functional naïve T-cell pool in the patient thymus. However, it is challenging to produce HTLPs in the high numbers required to meet clinical needs. Here, we found that adding tumor necrosis factor alpha (TNFα) to a DL-4-based culture system led to the generation of a large number of nonmodified or genetically modified HTLPs possessing highly efficient in vitro and in vivo T-cell potential from either CB HSPCs or mPB HSPCs through accelerated T-cell differentiation and enhanced HTLP cell cycling and survival. This study provides a clinically suitable cell culture platform to generate high numbers of clinically potent nonmodified or genetically modified HTLPs for accelerating immune recovery after HSCT and for T-cell-based immunotherapy (including CAR T-cell therapy).},

keywords = {},

pubstate = {ppublish},

tppubtype = {article}

}

@article{Ingels2021,

title = {Treatment of a patient with severe cytomegalovirus (CMV) infection after haploidentical stem cell transplantation with donor derived CMV specific T cells.},

author = {Joline Ingels and Saskia De Smet and Kelly Heyns and Nele Lootens and Jonas Segaert and Tom Taghon and Georges Leclercq and Karim Vermaelen and Evelyne Willems and Etienne Baudoux and Tessa Kerre and Frédéric Baron and Bart Vandekerckhove},

doi = {10.1080/17843286.2020.1752446},

issn = {2295-3337},

year  = {2021},

date = {2021-01-01},

journal = {Acta clinica Belgica},

volume = {76},

pages = {482--486},

abstract = {Cytomegalovirus (CMV) infection is one of the most common complications in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients. The classic antiviral treatments have shown clinical efficacy but are often associated with drug resistance. Reconstitution of CMV-specific cellular immunity is essential in controlling CMV infection; therefore, adoptive transfer of CMV-specific T cells is a promising treatment option. We treated a patient with a multidrug resistant CMV infection after haploidentical HSCT with CMV-specific T cells. The T cells were derived from the HSCT donor who was CMV seropositive. We generated the T cells by a short-term Good Manufacturing Practice (GMP) grade protocol in which a leukapheresis product of the HSCT donor was stimulated with the immunodominant antigen pp65 and interferon-γ secreting cells were isolated. A total of 5 × 10  T cells were administered to the patient within 30 hours after leukapheresis. The patient was closely monitored for reconstitution of antiviral T cell immunity and viral replication after adoptive T cell transfer. We observed an in vivo expansion of both CD4 and CD8 CMV-specific T cells associated with a significant decrease in viral burden and clinical improvement. This case report further supports the feasibility and effectiveness of adoptive donor T cell transfer for the treatment of drug resistant CMV infections after allo-HSCT.},

keywords = {},

pubstate = {ppublish},

tppubtype = {article}

}