In vitro–differentiated T/natural killer–cell progenitors derived from human CD34+ cells mature in the thymus

Meek, Bob; Cloosen, Silvie; Borsotti, Chiara; Elssen, Catharina H. M. J. Van; Vanderlocht, Joris; Schnijderberg, Melanie C. A.; Poel, Marjolein W. M. van der; Leewis, Bas; Hesselink, Reinout P.; Manz, Markus G.; Katsura, Yoshiteru; Kawamoto, Hiroshi; Germeraad, Wilfred T.V.; Bos, Gerard M.J.

doi:10.1182/blood-2009-05-223990

Cited by 30 publications

(52 citation statements)

References 17 publications

(20 reference statements)

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“…Furthermore, questions remain about the functionality of these in vitro-matured T cells regarding their MHC-restriction and some phenotypic abnormalities [8]. In accordance with our data, Meek et al recently reported the same maturation arrest at the T/NK-progenitor cell level using a DLL-4 over-expressing stroma cell line [7]. CD34 …”

Section: Cd7supporting

confidence: 89%

“…1 lymphoid progenitors after intrahepatic transplantation in neonatal mice [6,7]. However, in these two models, no extrathymic mature T cells could be detected, so it remained questionable whether a single intravenous injection of CTLPs can lead to peripheral T-cell engraftment.…”

Section: Cd7mentioning

confidence: 99%

“…1B and C). Although two groups have reported the generation of mature single-positive T cells in OP9/DLL co-cultures [3,8], others failed [7]. Furthermore, questions remain about the functionality of these in vitro-matured T cells regarding their MHC-restriction and some phenotypic abnormalities [8].…”

Section: Cd7mentioning

confidence: 99%

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Pre‐differentiated human committed T‐lymphoid progenitors promote peripheral T‐cell re‐constitution after stem cell transplantation in immunodeficient mice

et al. 2011

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T‐cell re‐constitution after allogeneic stem cell transplantation (alloSCT) is often dampened by the slow differentiation of human peripheral blood CD34+ (huCD34+) hematopoietic stem cells (HSCs) into mature T cells. This process may be accelerated by the co‐transfer of in vitro‐pre‐differentiated committed T/NK‐lymphoid progenitors (CTLPs). Here, we analysed the developmental potential of huCD34+ HSCs compared with CTLPs from a third‐party donor in a murine NOD‐scid IL2Rγnull model of humanised chimeric haematopoiesis. CTLPs (CD34+lin−CD45RA+CD7+) could be generated in vitro within 10 days upon co‐culture of huCD34+ or cord blood CD34+ (CB‐CD34) HSCs on murine OP9/N‐DLL‐1 stroma cells but not in a novel 3‐D cell‐culture matrix with DLL‐1low human stroma cells. In both in vitro systems, huCD34+ and CB‐CD34+ HSCs did not give rise to mature T cells. Upon transfer into 6‐wk‐old immune‐deficient mice, CTLPs alone did not engraft. However, transplantation of CTLPs together with huCD34+ HSCs resulted in rapid T‐cell engraftment in spleen, bone marrow and thymus at day 28. Strikingly, at this early time point mature T cells originated exclusively from CTLPs, whereas descendants of huCD34+ HSCs still expressed a T‐cell‐precursor phenotype (CD7+CD5+CD1a+/−). This strategy to enhance early T‐cell re‐constitution with ex vivo‐pre‐differentiated T‐lymphoid progenitors could bridge the gap until full T‐cell recovery in severely immunocompromised patients after allogeneic stem cell transplantation.

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Section: Cd7supporting

confidence: 89%

Section: Cd7mentioning

confidence: 99%

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Pre‐differentiated human committed T‐lymphoid progenitors promote peripheral T‐cell re‐constitution after stem cell transplantation in immunodeficient mice

et al. 2011

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“…Nevertheless, it appears that this population of CLPs is skewed toward a B lymphocyte fate, whereas cord blood progenitors with a CD34þCD7þCD45RAþ phenotype express T/NK cell lineage-affiliated genes and show enhanced T lineage differentiation potential [44]. Furthermore, recent studies have demonstrated that following ex vivo Notch ligand stimulation of CD34þ progenitors, it is the differentiated CD34þCD7þ CD45RAþ CLP subset that displays augmented in vivo thymus colonization and a more rapid T-cell differentiation than conventional CD34þ progenitors [45][46][47]. Thus, the precursors that settle the human thymus under physiological conditions are likely to share this CD34þCD7þCD45RAþ phenotype.…”

Section: Hematopoietic Precursor Differentiation Within the Thymusmentioning

confidence: 99%

Concise Review: Hematopoietic Stem Cell Transplantation: Targeting the Thymus

2013

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Allogeneic hematopoietic stem cell (HSC) transplantation can cure patients suffering from diverse genetic and acquired diseases as well as cancers. Nevertheless, under conditions where T-cell reconstitution is critical, the entry of donor progenitors into the thymus remains a major bottleneck. It is assumed that following the intravenous injection of HSC, they first home to the BM. More committed progenitors can then be exported to the thymus in response to a myriad of signals regulating thymus seeding. Notably although, the thymus is not continually receptive to the import of hematopoietic progenitors. Furthermore, as stem cells with self-renewing capacity do not take up residence in the thymus under physiological conditions, the periodic colonization of the thymus is essential for the sustained differentiation of T lymphocytes. As such, we and others have invested significant efforts into exploring avenues that might foster a long-term thymus-autonomous differentiation. Here, we review strategic approaches that have resulted in long-term T-cell differentiation in immunodeficient (SCID) mice, even across histocompatibility barriers. These include the forced thymic entry of BM precursors by their direct intrathymic injection as well as the transplantation of neonatal thymi. The capacity of the thymus to support hematopoietic progenitors with renewal potential will hopefully promote the development of new therapeutic strategies aimed at enhancing T-cell differentiation in patients undergoing HSC transplantation.

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“…NK-cell cytotoxicity was analyzed by a flow cytometry-based kill assay as described previously [43]. Briefly, NK cells were incubated for 24 h with either DC supernatant, medium alone or medium containing 1000 U/mL IL-2 (Proleukin).…”

Section: Nk-cell Cytotoxicity Assaymentioning

confidence: 99%

Klebsiella pneumoniae‐triggered DC recruit human NK cells in a CCR5‐dependent manner leading to increased CCL19‐responsiveness and activation of NK cells

et al. 2010

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Besides their role in destruction of altered self-cells, NK cells have been shown to potentiate T-cell responses by interacting with DC. To take advantage of NK-DC crosstalk in therapeutic DC-based vaccination for infectious diseases and cancer, it is essential to understand the biology of this crosstalk. We aimed to elucidate the in vitro mechanisms responsible for NK-cell recruitment and activation by DC during infection. To mimic bacterial infection, DC were exposed to a membrane fraction of Klebsiella pneumoniae, which triggers TLR2/4. DC matured with these bacterial fragments can actively recruit NK cells in a CCR5-dependent manner. An additional mechanism of DC-induced NK-cell recruitment is characterized by the induction of CCR7 expression on CD56 dim CD16 1 NK cells after physical contact with membrane fraction of K. pneumoniae-matured DC, resulting in an enhanced migratory responsiveness to the lymph node-associated chemokine CCL19. Bacterial fragment-matured DC do not only mediate NK-cell migration but also meet the prerequisites needed for augmentation of NK-cell cytotoxicity and IFN-c production, the latter of which contributes to Th1 polarization.Key words: CCR5 . CCR7 . NK-DC interaction . Th1 polarization Supporting Information available online Introduction NK cells are important effector cells in the innate immune response against virally infected or malignantly transformed cells and their cytotoxicity is regulated by a delicate balance of inhibitory and activating signals [1]. Recent studies suggest that the interplay between NK cells and DC, the specialized antigenpresenting cell of the innate immune system [2], is critical in shaping the adaptive immune response [3]. This concept originates from several lines of evidence including: the discovery of NK cells colocalizing with DC in the T-cell areas of lymph nodes [4,5], the coupling of NK-cell recruitment to lymph nodes Ã These authors contributed equally to this work. 3138with the induction of more potent Th1 skewing [3], and the identification of NK-cell subpopulations with helper properties [6]. Although the exact mechanisms of NK-DC interaction remain to be elucidated, increasing evidence supports the importance of bidirectional NK-DC crosstalk [7,8].On the one hand, NK-DC crosstalk is characterized by the capacity of activated NK cells to induce DC maturation with elevated IL-12p70 production and subsequently an increased capacity to induce Th1 and CTL responses [9]. This NK-induced DC maturation depends at least in part on soluble factors such as and as well as on engagement of the natural cytotoxicity triggering receptor 30 [12]. Moreover, NK cells control the quality of the adaptive immune response by natural cytotoxicity triggering receptor 30-mediated lysis of immature or inadequately matured DC [13], enabling only fully mature DC to migrate into lymph nodes and subsequently prime T cells. On the other hand, DC are able to induce NK-cell proliferation, augmentation of cytotoxicity and cytokine secretion [8]. The DC-induced modulati...

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In vitro–differentiated T/natural killer–cell progenitors derived from human CD34+ cells mature in the thymus

Cited by 30 publications

References 17 publications

Pre‐differentiated human committed T‐lymphoid progenitors promote peripheral T‐cell re‐constitution after stem cell transplantation in immunodeficient mice

Pre‐differentiated human committed T‐lymphoid progenitors promote peripheral T‐cell re‐constitution after stem cell transplantation in immunodeficient mice

Concise Review: Hematopoietic Stem Cell Transplantation: Targeting the Thymus

Klebsiella pneumoniae‐triggered DC recruit human NK cells in a CCR5‐dependent manner leading to increased CCL19‐responsiveness and activation of NK cells

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