title: Fine-scale staging of T cell lineage commitment in adult mouse thymus.
abstract: T cell development is marked by the loss of alternative lineage choices accompanying specification and commitment to the T cell lineage. Commitment occurs between the CD4 and CD8 double-negative (DN) 2 and DN3 stages in mouse early T cells. To determine the gene regulatory changes that accompany commitment, we sought to distinguish and characterize the earliest committed wild-type DN adult thymocytes. A transitional cell population, defined by the first downregulation of surface c-Kit expression, was found to have lost the ability to differentiate into dendritic cells and NK cells when cultured without Notch-Delta signals. In the presence of Notch signaling, this subset generates T lineage descendants in an ordered precursor-product relationship between DN2, with the highest levels of surface c-Kit, and c-Kit-low DN3 cells. These earliest committed cells show only a few differences in regulatory gene expression, compared with uncommitted DN2 cells. They have not yet established the full expression of Notch-related and T cell differentiation genes characteristic of DN3 cells before beta selection. Instead, the downregulation of select stem cell and non-T lineage genes appears to be key to the extinction of alternative lineage choices.
authors.affiliation: Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA. yui@caltech.edu
authors.forename: Mary A
authors.initials: MA
authors.lastname: Yui
authors.forename: Ni
authors.initials: N
authors.lastname: Feng
authors.forename: Ellen V
authors.initials: EV
authors.lastname: Rothenberg
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics / Q000276:immunology*; D018920:Coculture Techniques; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D051881:Receptor, Notch1 / Q000235:genetics / Q000502:physiology; D013234:Stem Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
chemical_list: C497762:Notch1 protein, mouse; D051881:Receptor, Notch1