Mechanisms of T Cell Development and Transformation

Ute Koch, Freddy Radtke
2011
Article

Résumé

T cells are the key mediators in cell-mediated immunity. Their development and maturation involve a complex variety of interactions with nonlymphoid cell products and receptors. Highly specialized to defend against bacterial and viral infections, T cells also mediate immune surveillance against tumor cells and react to foreign tissues. T cell progenitors originate in the bone marrow and, through a series of defined and coordinated developmental stages, enter the thymus, differentiate, undergo selection, and eventually mature into functional T cells. The steps in this process are regulated through a complex transcriptional network, specific receptor-ligand pair interactions, and sensitization to trophic factors, which mediate the homing, proliferation, survival, and differentiation of developing T cells. This review examines the processes and pathways involved in the highly orchestrated development of T cell fate specification under physiological as well as pathological conditions.

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https://infoscience.epfl.ch/record/178477?ln=fr

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Ute Koch, Freddy Radtke
2011
Article

Résumé

Official source

https://infoscience.epfl.ch/record/178477?ln=fr

À propos de ce résultat

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Notch signaling in lymphopoiesis

Freddy Radtke

Notch signaling regulates many cell fate decisions during development of multi-cellular organisms. Signals initiated by Notch influence a wide variety of processes that include lineage specification, cell survival and proliferation, and border formation. During development of the immune system, Notch has been shown to influence the fate of both hematopoietic stem cells (HSCs) and committed progenitors. Notch appears to play an especially important role in the development of cells that mediate acquired immunity where Notch influences multiple aspects of T and B cell development. In this review, we will focus on the potential functions of Notch signaling during lymphoid development.

2003

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Notch1 deficiency dissociates the intrathymic development of dendritic cells and T cells

Michel Aguet, Freddy Radtke, Anne Wilson

Thymic dendritic cells (DCs) form a discrete subset of bone marrow (BM)-derived cells, the function of which is to mediate negative selection of autoreactive thymocytes. The developmental origin of thymic DCs remains controversial. Although cell transfer studies support a model in which T cells and thymic DCs develop from the same intrathymic pluripotential precursor, it remains possible that these two types of cells develop from independent intrathymic precursors. Notch proteins are cell surface receptors involved in the regulation of cell fate specification. We have recently reported that T cell development in inducible Notch1-deficient mice is severely impaired at an early stage, before the expression of T cell lineage markers. To investigate whether development of thymic DCs also depends on Notch1, we have constructed mixed BM chimeric mice. We report here that thymic DC development from Notch1(-/)- BM precursors is absolutely normal (in terms of absolute number and phenotype) in this competitive situation, despite the absence of Notch1(-/)- T cells. Furthermore, we find that peripheral DCs and Langerhans cells are also not affected by Notch1 deficiency. Our results demonstrate that the development of DCs is totally independent of Notch1 function, and strongly suggest a dissociation between intrathymic T cell and DC precursors.

2000

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Notch 1-deficient common lymphoid precursors adopt a B cell fate in the thymus

Freddy Radtke, Anne Wilson

We have recently reported that Notch 1, a member of the Notch multigene family, is essential for the development of murine T cells. Using a mouse model in which Notch 1 is inactivated in bone marrow (BM) precursors we have shown that B cells instead of T cells are found in the thymus of BM chimeras. However, it is not clear whether these B cells develop by default from a common lymphoid precursor due to the absence of Notch 1 signaling, or whether they arise as a result of perturbed migration of BM-derived B cells and/or altered homeostasis of normal resident thymic B cells.In this report we show that Notch 1-deficient thymic B cells resemble BM B cells in phenotype and turnover kinetics and are located predominantly in the medulla and corticomedullary junction. Peripheral blood lymphocyte analysis shows no evidence of recirculating Notch1(-/)- BM B cells. Furthermore, lack of T cell development is not due to a failure of Notch1(-/)- precursors to home to the thymus, as even after intrathymic reconstitution with BM cells, B cells instead of T cells develop from Notch 1-deficient precursors. Taken together, these results provide evidence for de novo ectopic B cell development in the thymus, and support the hypothesis that in the absence of Notch 1 common lymphoid precursors adopt the default cell fate and develop into B cells instead.

2001

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