Inactivation of Notch1 in immature thymocytes does not perturb CD4 or CD8 T cell development

Wolfer, Anita; Bakker, Talitha R.; Wilson, Anne; Nicolas, Michaël; Ioannidis, Vassilios; Littman, Dan R.; Wilson, Christopher; Held, Werner; MacDonald, H. Robson; Radtke, Freddy

doi:10.1038/85294

Cited by 269 publications

(264 citation statements)

References 29 publications

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“…Models using inducible Notch 1 gene deletion suggested that Notch plays a role at least throughout the DN stages [26]. However, deletion of Notch 1 at the late DN stage does not impair normal thymocyte development [27]. Human thymocyte CD34 1 TN population studied here is a mixture of different thymocyte precursors but contained a large majority of CD1a 1 CD5 1 CD4 À cells (data not shown) corresponding to the DN3 stage in mice.…”

Section: Discussionmentioning

confidence: 72%

Notch ligands potentiate IL‐7‐driven proliferation and survival of human thymocyte precursors

et al. 2009

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Notch and IL-7 are both well-characterized factors involved in T-cell development. In contrast to the mouse model, their precise requirements in the differentiation and/or proliferation of various stages of human thymic development have not been fully explored. Here, we demonstrate that IL-7 alone is sufficient to induce the differentiation of ex vivoimmature single positive (ISP) (sCD3 À CD4 1 CD8 À ) and double positive (DP) (sCD3 À CD4 1 CD8 1 ) human thymic precursors to mature DP expressing sCD3 (sCD3 1 CD4 1 CD8 1 ). We show that activation of Notch signaling by its ligands Delta-1 or Delta-4 potentiates IL-7-driven proliferation and survival of CD34 1 TN and to a lesser extent of CD4 1 ISP precursors. This effect of Notch is related to a sustained induction of IL-7 receptor a chain expression on thymocytes through a decreased methylation of its gene promoter. Thus, we show here that proliferation and differentiation of T-cell precursors are differentially modulated by IL-7 depending on the presence or absence of external signals. These results may have important implications for the clinical use of this cytokine as a strategy aimed at improving immune restoration.

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Section: Discussionmentioning

confidence: 72%

Notch ligands potentiate IL‐7‐driven proliferation and survival of human thymocyte precursors

et al. 2009

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“…In addition, our evidence indicates that Notch signaling is ongoing throughout the CD4 Ϫ 8 Ϫ stage, and we have shown that such signaling, at least within unseparated E15 CD4 Ϫ 8 Ϫ thymocytes, is dependent upon interaction with thymic epithelial cells. As the currently available inducible Notch knockout animals result in deletion either before or toward the end of the DN stage (8,29,30), the physiological relevance of this activity remains to be determined. Likewise, the roles of individual Notch ligands expressed by thymic epithelium in regulating intrathymic Notch activity for T/B lineage choice and for other lineage choices (e.g., ␣␤/␥␦ vs NK) within the T pathway are important issues still to be resolved.…”

Section: Discussionmentioning

confidence: 99%

Entry into the Thymic Microenvironment Triggers Notch Activation in the Earliest Migrant T Cell Progenitors

Harman

Jenkinson

Anderson

2003

The Journal of Immunology

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Interactions between T cell precursors and thymic stromal cells are essential during thymocyte development. However, the role of the thymus in initial commitment of lymphoid progenitors to the T lineage remains controversial, with data providing evidence for both extra- and intrathymic commitment mechanisms. In this context, it is clear that Notch1 is an important mediator during initiation of T cell development. Here we have analyzed the mechanisms regulating Notch activation in lymphoid precursors at extrathymic sites and in the thymus, including stages representing the first wave of embryonic thymus colonization on embryonic day 12 of gestation. We show that Notch activation in migrant lymphoid precursors requires entry into the thymic microenvironment where they are exposed to Notch ligands expressed by immature thymic epithelial cells. Moreover, continued Notch signaling in such precursors requires sustained interactions with Notch ligands. Collectively, these findings suggest a role for Notch in an intrathymic mechanism of T cell lineage commitment involving sustained interactions with Notch ligand bearing thymic epithelium.

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“…Although two distinct strains of conditional Notch1-KO mice share no defects in the generation of mature SP thymocytes (18,19), overexpression experiments have suggested that constitutively active Notch1 biases thymocyte development toward the CD8 lineage or even prevents the maturation of SP cells completely (20 -23). In the light of this ongoing debate, we have generated transgenic rats expressing Notch1IC in the thymus.…”

Section: Discussionmentioning

confidence: 99%

“…However, it appears that these differences partly derive from the individual experimental approaches taken. Two strains of conditional Notch1-knockout (KO) mice where the gene had been deleted at different time points during the DN stage of thymocyte development failed to reveal any effect on the generation of SP thymocytes (18,19). Thus, Notch1 does not play an essential, nonredundant role in this lineage decision.…”

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confidence: 99%

Sustained Pre-TCR Expression in Notch1IC-Transgenic Rats Impairs T Cell Maturation and Selection

Brandt

Kwon

Hünig

et al. 2005

The Journal of Immunology

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Notch1 is involved in directing cell fate decisions in a variety of developmental scenarios. Extending previous experiments in mice, we generated transgenic rats expressing the intracellular domain of Notch1 in the thymus. Importantly, this leads to sustained expression of the pre-TCR throughout thymocyte development, accompanied by a reduction of αβTCR complexes. In addition, re-expression of RAG-1 and RAG-2 in TCRβ+ cells is impaired, and the Vα repertoire is altered. Consequently, thymocytes in transgenic rats do not undergo positive selection and largely fail to progress to the single positive stage. According to our model, the previously reported effects of Notch1 on the CD4/CD8 cell fate decision may be explained by a differential sensitivity of the two lineages toward altered TCR signaling.

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Inactivation of Notch1 in immature thymocytes does not perturb CD4 or CD8 T cell development

Cited by 269 publications

References 29 publications

Notch ligands potentiate IL‐7‐driven proliferation and survival of human thymocyte precursors

Notch ligands potentiate IL‐7‐driven proliferation and survival of human thymocyte precursors

Entry into the Thymic Microenvironment Triggers Notch Activation in the Earliest Migrant T Cell Progenitors

Sustained Pre-TCR Expression in Notch1IC-Transgenic Rats Impairs T Cell Maturation and Selection

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