Abstract
The first checkpoint during T cell development, known as beta selection, requires the successful rearrangement of the TCR-beta gene locus. Notch signaling has been implicated in various stages during T lymphopoiesis. However, it is unclear whether Notch receptor-ligand interactions are necessary during beta selection. Here, we show that pre-TCR signaling concurrent with Notch receptor and Delta-like-1 ligand interactions are required for the survival, proliferation, and differentiation of mouse CD4(-)CD8(-) thymocytes to the CD4(+)CD8(+) stage. Furthermore, we address the minimal signaling requirements underlying beta selection and show a hierarchical positioning of key proximal signaling molecules. Collectively, our results demonstrate an essential role for Notch receptor-ligand interactions in enabling the autonomous signaling capacity of the pre-TCR complex.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Antibodies, Monoclonal / administration & dosage
-
CD3 Complex / immunology
-
Cell Differentiation / genetics
-
Cell Differentiation / immunology
-
Cell Division / genetics
-
Cell Division / immunology
-
Cell Line
-
Coculture Techniques
-
DNA-Binding Proteins / deficiency
-
DNA-Binding Proteins / genetics
-
Fetus
-
Gene Rearrangement, beta-Chain T-Cell Antigen Receptor
-
Genes, T-Cell Receptor beta / physiology
-
Intracellular Signaling Peptides and Proteins
-
Ligands
-
Membrane Glycoproteins / biosynthesis
-
Membrane Glycoproteins / genetics
-
Membrane Glycoproteins / physiology*
-
Membrane Proteins / metabolism
-
Membrane Proteins / physiology*
-
Mice
-
Mice, Knockout
-
Protein Precursors / biosynthesis
-
Protein Precursors / genetics
-
Protein Precursors / physiology*
-
Receptors, Antigen, T-Cell, alpha-beta
-
Receptors, Notch
-
Signal Transduction / genetics
-
Signal Transduction / immunology*
-
Stromal Cells / immunology
-
Stromal Cells / metabolism
-
T-Lymphocyte Subsets / cytology*
-
T-Lymphocyte Subsets / immunology
-
T-Lymphocyte Subsets / metabolism
-
Thymus Gland / cytology*
-
Thymus Gland / immunology*
-
Thymus Gland / metabolism
Substances
-
Antibodies, Monoclonal
-
CD3 Complex
-
DNA-Binding Proteins
-
Intracellular Signaling Peptides and Proteins
-
Ligands
-
Membrane Glycoproteins
-
Membrane Proteins
-
Protein Precursors
-
Rag2 protein, mouse
-
Receptors, Antigen, T-Cell, alpha-beta
-
Receptors, Notch
-
V(D)J recombination activating protein 2
-
delta protein
-
pre-T cell receptor alpha