Dissertation

Lineage commitment in T cell development

Itano, Andrea Akemi

1999

Overview

Although CD4+ and CD8+ T cells have very different peripheral effector functions, both cell types are derived from a common progenitor cell that develops in the thymus. This precursor, which expresses both CD4 and CD8, must at some point choose between the CD4 and CD8 lineages. In order to elucidate the mechanism by which thymocytes choose between the CD4 and CD8 lineages, we undertook a kinetic analysis of the generation of mature T cells in TCR and co-receptor transgenic mice using BrdU labeling. We observed a surprisingly high efficiency of selection of mature cells. Our findings support an instructional mechanism of lineage commitment in which signals through the T cell antigen receptor bias developing thymocytes towards one lineage or the other. Recent experiments have demonstrated that the Notch signaling pathway is also involved in both the CD4/CD8 lineage choice as well as the earlier fate choice between the γδ and αβ T lineages, and have suggested that Notch and TCR signals are integrated by the developing thymocytes during lineage commitment. In order to better understand the role of Notch in thymic development, we characterized the thymic development in mice mutant for Jagged 2 and Delta 3, two Notch ligands expressed in the thymus. We determined that the previously observed reduction in γδ T cells in mice deficient for Jagged 2 was due to a specific block in the development of Vγ3 + γδ T cells in the thymus. Delta 3 may also contribute to the generation of these cells. Our observations demonstrate that Notch signaling is involved in the development of a fetal lineage of γδ T cells. In addition to characterizing the effects of mutations in Notch ligands, we generated transgenic mice constitutively expressing full-length and truncated forms of Jagged 2 under the control of a thymocyte specific promoter. We observed no alteration of either the γδ/αβ or CD4/CD8 lineage choices, as well as normal numbers of Vγ3+ cells, in mice expressing high levels of either a full-length or truncated Jagged 2 protein. These results are possibly explained by the involvement of down-stream modulators of Notch signaling, such as Numb or Fringe, in thymic development.

• Publisher: ProQuest Dissertations & Theses
• Subject: Cellular biology / Molecular biology
• ISBN: 9780599711891, 0599711892