scholarly journals Notch ligands Delta1 and Jagged1 transmit distinct signals to T-cell precursors

Blood ◽  
2005 ◽  
Vol 105 (4) ◽  
pp. 1440-1447 ◽  
Author(s):  
Sophie M. Lehar ◽  
James Dooley ◽  
Andrew G. Farr ◽  
Michael J. Bevan
Keyword(s):  
T Cell ◽  
Stromal Cells ◽  
Notch Pathway ◽  
Cell Lineage ◽  
Thymocyte Development ◽  
Thymic Development ◽  
T Cell Progenitors ◽  
Notch Ligands ◽  
Immature Thymocytes

AbstractSignaling through the Notch pathway plays an essential role in inducing T-lineage commitment and promoting the maturation of immature thymocytes. Using an in vitro culture system, we show that 2 different classes of Notch ligands, Jagged1 or Delta1, transmit distinct signals to T-cell progenitors. OP9 stromal cells expressing either Jagged1 or Delta1 inhibit the differentiation of DN1 thymocytes into the B-cell lineage, but only the Delta1-expressing stromal cells promote the proliferation and maturation of T-cell progenitors through the early double-negative (DN) stages of thymocyte development. Whereas the majority of bone marrow–derived stem cells do not respond to Jagged1 signals, T-cell progenitors respond to Jagged1 signals during a brief window of their development between the DN1 and DN3 stages of thymic development. During these stages, Jagged1 signals can influence the differentiation of immature thymocytes along the natural killer (NK) and γδ T-cell lineages.

scholarly journals TNF activation of NF-κB is essential for development of single-positive thymocytes

2016 ◽  
Vol 213 (8) ◽  
pp. 1399-1407 ◽  
Author(s):  
Louise V. Webb ◽  
Steven C. Ley ◽  
Benedict Seddon
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Lineage ◽  
Cell Receptor ◽  
Thymocyte Development ◽  
Thymic Development ◽  
Survival And Development ◽  
Single Positive ◽  
Tcr Activation

NF-κB activation has been implicated at multiple stages of thymic development of T cells, during which it is thought to mediate developmental signals originating from the T cell receptor (TCR). However, the Card11–Bcl10–Malt1 (CBM) complex that is essential for TCR activation of NF-κB in peripheral T cells is not required for thymocyte development. It has remained unclear whether the TCR activates NF-κB independent of the CBM complex in thymocyte development or whether another NF-κB activating receptor is involved. In the present study, we generated mice in which T cells lacked expression of both catalytic subunits of the inhibitor of κB kinase (IKK) complex, IKK1 and IKK2, to investigate this question. Although early stages of T cell development were unperturbed, maturation of CD4 and CD8 single-positive (SP) thymocytes was blocked in mice lacking IKK1/2 in the T cell lineage. We found that IKK1/2-deficient thymocytes were specifically sensitized to TNF-induced cell death in vitro. Furthermore, the block in thymocyte development in IKK1/2-deficient mice could be rescued by blocking TNF with anti-TNF mAb or by ablation of TNFRI expression. These experiments reveal an essential role for TNF activation of NF-κB to promote the survival and development of single positive T cells in the thymus.

Stepwise Development of Committed Progenitors in the Bone Marrow That Generate Functional T Cells in the Absence of the Thymus.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3300-3300
Author(s):  
Sussan Dejbakhsh-Jones ◽  
Marcos E. Garcia-Ojeda ◽  
Devavanii Chatterjea ◽  
Aditi Mukhopadhyay ◽  
Irving L. Weissman ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Cell Lineage ◽  
Murine Cytomegalovirus ◽  
Lymphoid Tissues ◽  
Mouse Bone Marrow ◽  
Generate Functional ◽  
T Cell Progenitors

Abstract We identified committed T cell progenitors (CTPs) in the mouse bone marrow that have not rearranged the TCR β gene, express a variety of genes associated with commitment to the T cell lineage including GATA-3 and TCF-1, Cβand Id2, and show a surface marker pattern (CD44+CD25-CD24+CD5-) that is similar to the earliest T cell progenitors in the thymus. More mature committed intermediate progenitors (CIPs) in the marrow have rearranged the TCR gene loci, express Vαand Vβgenes as well as CD3ε, but do not express surface TCR or CD3 receptors. CTPs, but not progenitors from the thymus, reconstituted the αβ T cells in the lymphoid tissues of athymic nu/nu mice. These reconstituted T cells vigorously secreted IFN- γ after stimulation in vitro, and protected the mice against lethal infection with murine cytomegalovirus (MCMV). Also CTPs from the parent strain can reconstitute an F1 MHC haplotype mismatched host. In conclusion, CTPs in wild-type bone marrow can generate functional T cells via an extrathymic pathway.

scholarly journals Phenotypic plasticity of T cell progenitors upon exposure to Notch ligands

2006 ◽  
Vol 203 (8) ◽  
pp. 1977-1984 ◽  
Author(s):  
Andreas Krueger ◽  
Annette I. Garbe ◽  
Harald von Boehmer
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Stromal Cells ◽  
Regulatory Elements ◽  
Double Negative ◽  
Phenotypic Changes ◽  
Functional Potential ◽  
T Cell Progenitors ◽  
Notch Ligands

Despite many efforts, the nature of thymic immigrants that give rise to T cells has remained obscure, especially since it became known that extrathymic lineage-negative, Sca-1–positive, c-kit high progenitor cells differ from intrathymic early T cell progenitors (ETPs) by functional potential and dependence on Notch signaling. After our observation that intrathymic T cell precursors expressing a human CD25 reporter under control of pre-TCRα regulatory elements almost exclusively have the ETP phenotype, we have analyzed the phenotypic changes of reporter-expressing common lymphoid progenitor (CLP) cells in the bone marrow when cultured on Delta-like 1–expressing stromal cells. We note that these quickly adopt the phenotype of double negative (DN)2 thymocytes with little display of the ETP phenotype. Our data suggest that common lymphoid progenitor (CLP) cells could be responsible for the rapid reconstitution of thymus function after bone marrow transplantation since CLP cells in the blood have the capacity to rapidly enter the thymus and become DN2 thymocytes.

CBFB Is Required for Early T Cell Development in the Thymus.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 648-648
Author(s):  
Ling Zhao ◽  
Jennifer L. Cannons ◽  
Stacie Anderson ◽  
Martha R. Kirby ◽  
Liping Xu ◽  
...  
Keyword(s):  
T Cell ◽  
Bone Formation ◽  
Fusion Gene ◽  
T Cell Development ◽  
Cell Lineage ◽  
Cell Development ◽  
Dominant Negative ◽  
Compound Heterozygous ◽  
Thymocyte Development

Abstract Runx1 and Runx3 play important roles in early T cell development. Runx1 is required in the development of double negative cells. Runx1 is also required to repress CD4 expression in DN cells while Runx 3 is essential for epigenetic silencing of CD4 expression in CD8 cells. Both Runx1 and Runx3 are required for CD8 cell development. Because Cbfβ heterodimerizes with both Runx1 and Runx3, we hypothesized that Cbfb is also important in T cell development. To address this issue we analyzed transgenic mouse models with three Cbfb alleles. The first is a null allele for Cbfb and embryos homozygous for this allele die in midgestation due to failure of definitive hematopoiesis and hemorrhage. The second one is a GFP knockin. This Cbfb-GFP allele is a hypomorphic one in that the fusion protein Cbfβ-GFP produced from the allele behaves similarly as the wildtype Cbfβ protein but RNA and protein production from the allele is lower than that of the wildtype allele. Interestingly, AGM hematopoiesis is relatively normal and there is no hemorrhage in the CbfbGFP/GFP embryos, which die at birth due to bone formation defects. The third model is our knock-in mouse model expressing Cbfb-MYH11, the fusion gene found in human AML MeEo with inv (16)(p13; q22). Heterozygous knock-in mice had a phenotype identical to that of the Cbfb and Runx1 null mice, suggesting that the fusion gene Cbfb-MYH11 functions in a dominant-negative manner. We conditionally expressed the Cbfb-MYH11 fusion gene in T cells by using Cre-lox recombination with a floxed Cbfb-MYH11 allele and a Lck-Cre transgene, which starts to express the Cre enzyme at the DN2 stage. By analyzing embryos compound-heterozygous for the null and the hypomorphic GFP knockin alleles (Cbfb−/GFP), we found that CD4 expression was derepressed and thymocyte development was blocked at DN1 and DN2 stages in E17.5 Cbfb−/GFP embryos, which also had much smaller thymi with reduced cellularity compared to their litter mate controls. Further studies on cell proliferation and apoptosis indicated that increased cell death might account for the reduced cellularity. The compound heterozygous Cbfb−/GFP mice died at birth with severe bone formation defects. The Tg(Lck-Cre)/conditional Cbfb-MYH11 mice were viable. In adult thymus, Cbfb-MYH11 expression led to a 10-fold reduction in thymocyte numbers, resulting from both impaired survival of CD4+CD8+ thymocytes (similar as in Cbfb−/GFP embryos) and a differentiation block at DN3 stage. The reduced cellularity could be rescued by over expression of Bcl2 through crossing with Tg(Lck-hBcl2) mice. Cbfb-MYH11 did not derepress CD4 expression in the thymus even though it did so in reporter assays in vitro, which could be due to incomplete Cre-lox reaction, or that Cbfb-MYH11 acts more than just a pure dominant negative. Our data suggest that Cbfβ is critical for several stages of T cell development and may help to explain why CBFB-MYH11+ cells cannot be detected in the T cell lineage in AML patients with this fusion gene.

scholarly journals T Cells Develop Normally in the Absence of both Deltex1 and Deltex2

2006 ◽  
Vol 26 (20) ◽  
pp. 7358-7371 ◽  
Author(s):  
Sophie M. Lehar ◽  
Michael J. Bevan
Keyword(s):  
T Cells ◽  
T Cell ◽  
Notch Signaling ◽  
Negative Regulator ◽  
Thymocyte Development ◽  
Double Knockout ◽  
Vitro Assay ◽  
T Cell Progenitors ◽  
Related Proteins

ABSTRACT Deltex1, Deltex2, and Deltex4 form a family of related proteins that are the mammalian homologues of Drosophila Deltex, a known regulator of Notch signals. Deltex1 is highly induced by Notch signaling in thymocytes, and overexpression of Deltex1 in T-cell progenitors can block Notch signals, suggesting that Deltex1 may play an important role in regulating Notch signals during T-cell development. A recent report found that T cells develop normally in mice carrying a targeted deletion in the Deltex1 gene (S. Storck, F. Delbos, N. Stadler, C. Thirion-Delalande, F. Bernex, C. Verthuy, P. Ferrier, J. C. Weill, and C. A. Reynaud, Mol. Cell. Biol. 25: 1437-1445, 2005), suggesting that other Deltex homologues may compensate in Deltex1-deficient T cells. We generated mice that lack expression of both Deltex1 and Deltex2 by gene targeting and further reduced expression of Deltex4 in Deltex1/Deltex2 double-deficient T-cell progenitors using RNA interference. Using a sensitive in vitro assay, we found that Notch signaling is more potent in cells expressing lower levels of Deltex proteins. Nevertheless, we were unable to detect any significant defects in thymocyte maturation in Deltex1/Deltex2 double-knockout mice. Together these data suggest that Deltex can act as a negative regulator of Notch signals in T cells but that endogenous levels of Deltex1 and Deltex2 are not important for regulating Notch signals during thymocyte development.

scholarly journals Early T-cell progenitors are the major granulocyte precursors in the adult mouse thymus

Blood ◽  
2013 ◽  
Vol 121 (1) ◽  
pp. 64-71 ◽  
Author(s):  
Maria Elena De Obaldia ◽  
J. Jeremiah Bell ◽  
Avinash Bhandoola
Keyword(s):  
T Cell ◽  
Cell Lineage ◽  
Cell Repertoire ◽  
Mouse Thymus ◽  
Thymic Development ◽  
Genetic Ablation ◽  
Cell Lineages ◽  
Repertoire Selection

Abstract The mouse thymus supports T-cell development, but also contains non–T-cell lineages such as dendritic cells, macrophages, and granulocytes that are necessary for T-cell repertoire selection and apoptotic thymocyte clearance. Early thymic progenitors (ETPs) are not committed to the T-cell lineage, as demonstrated by both in vitro and in vivo assays. Whether ETPs realize non–T-cell lineage potentials in vivo is not well understood and indeed is controversial. In the present study, we investigated whether ETPs are the major precursors of any non–T-lineage cells in the thymus. We analyzed the development of these populations under experimental circumstances in which ETPs are nearly absent due to either abrogated thymic settling or inhibition of early thymic development by genetic ablation of IL-7 receptorα or Hes1. Results obtained using multiple in vivo approaches indicate that the majority of thymic granulocytes derive from ETPs. These data indicate that myelolymphoid progenitors settle the thymus and thus clarify the pathways by which stem cells give rise to downstream blood cell lineages.

Development of Thymic Microenvironments In Vitro Is Oxygen-dependent and Requires Permanent Presence of T-cell Progenitors

2003 ◽  
Vol 51 (9) ◽  
pp. 1225-1235 ◽  
Author(s):  
Wilfred T.V. Germeraad ◽  
Hiroshi Kawamoto ◽  
Manami Itoi ◽  
Yufei Jiang ◽  
Takashi Amagai ◽  
...  
Keyword(s):  
T Cell ◽  
Oxygen Pressure ◽  
Stromal Cells ◽  
Physical Contact ◽  
Cell Repertoire ◽  
Thymic Epithelium ◽  
High Oxygen Pressure ◽  
Thymic Stroma ◽  
T Cell Progenitors

Development of a mature T-cell repertoire in the thymus depends on lympho-stromal interaction between thymocytes and stromal cells. To facilitate intercellular contact, the epithelium in the thymus has differentiated into a unique three-dimensionally (3D)-oriented network. Here we analyze factors influencing induction and maintenance of the 3D configuration of the epithelial network in fetal thymic lobes in vitro. We show that the 3D configuration of the thymic stroma depends on (a) the oxygen pressure in vitro and (b) permanent physical contact between stromal cells and developing thymocytes. This latter feature is demonstrated by incubation of fetal thymic lobes with deoxyguanosine (d-Guo), inducing a 2D-organized thymic stroma, with thymic cysts appearing. Reconstitution of d-Guo-treated lobes with a limited number of flow-sorted T-cell progenitors restores the 3D configuration of the thymic epithelium, but only at high oxygen pressure. This study underlines the plasticity of thymic epithelium and shows that the unique organization of the thymic epithelium is dependent on both oxygen and crosstalk signals derived from developing thymocytes.

scholarly journals The Ubiquitously Expressed Csk Adaptor Protein Cbp Is Dispensable for Embryogenesis and T-Cell Development and Function

2005 ◽  
Vol 25 (23) ◽  
pp. 10533-10542 ◽  
Author(s):  
Marc-Werner Dobenecker ◽  
Christian Schmedt ◽  
Masato Okada ◽  
Alexander Tarakhovsky
Keyword(s):  
T Cell ◽  
Adaptor Protein ◽  
Regulatory Function ◽  
Loss Of Function ◽  
Thymic Development ◽  
Cell Functions ◽  
Carboxy Terminal ◽  
And Function

ABSTRACT Regulation of Src family kinase (SFK) activity is indispensable for a functional immune system and embryogenesis. The activity of SFKs is inhibited by the presence of the carboxy-terminal Src kinase (Csk) at the cell membrane. Thus, recruitment of cytosolic Csk to the membrane-associated SFKs is crucial for its regulatory function. Previous studies utilizing in vitro and transgenic models suggested that the Csk-binding protein (Cbp), also known as phosphoprotein associated with glycosphingolipid microdomains (PAG), is the membrane adaptor for Csk. However, loss-of-function genetic evidence to support this notion was lacking. Herein, we demonstrate that the targeted disruption of the cbp gene in mice has no effect on embryogenesis, thymic development, or T-cell functions in vivo. Moreover, recruitment of Csk to the specialized membrane compartment of “lipid rafts” is not impaired by Cbp deficiency. Our results indicate that Cbp is dispensable for the recruitment of Csk to the membrane and that another Csk adaptor, yet to be discovered, compensates for the loss of Cbp.

scholarly journals Developmentally regulated expression of CD3 components independent of clonotypic T cell antigen receptor complexes on immature thymocytes.

1994 ◽  
Vol 180 (4) ◽  
pp. 1375-1382 ◽  
Author(s):  
D L Wiest ◽  
K P Kearse ◽  
E W Shores ◽  
A Singer
Keyword(s):  
T Cells ◽  
T Cell ◽  
Biochemical Characterization ◽  
Severe Combined Immunodeficiency ◽  
Structural Basis ◽  
Thymocyte Development ◽  
Antibody Treatment ◽  
Receptor Complexes ◽  
Stage Of Development ◽  
Immature Thymocytes

CD3 signal transducing proteins are thought to be expressed on the surface of T cells only as part of clonotypic T cell receptor (TCR) complexes. Contrary to this paradigm, the present study describes surface expression of CD3 proteins independently of clonotypic TCR complexes, but only on immature thymocytes. Such novel clonotype-independent CD3 (CIC) complexes are composed primarily of CD3 gamma epsilon and secondarily of CD3 delta epsilon heterodimers that are independent of one another and are expressed on the cell surface in association with an unknown 90-100 kD protein termed CD3-associated protein (CD3AP). CIC complexes are expressed in normal mice on early thymocytes through the CD4+CD8+ stage of development, but not on mature peripheral T cells. Furthermore, CIC complexes are expressed by both TCR- severe combined immunodeficiency (SCID) thymocytes and thymoma cell lines, in the absence of any clonotypic chains. The isolation and biochemical characterization of surface CIC complexes provides a structural basis for the signaling effects of anti-CD3 epsilon antibody treatment in early thymocyte development.

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