Obligatory Role for Cooperative Signaling by Pre-TCR and Notch during Thymocyte Differentiation

• Published in: The Journal of immunology (1950) Vol. 172; no. 9; pp. 5230 - 5239
• Main Authors: Ciofani, Maria, Schmitt, Thomas M, Ciofani, Amelia, Michie, Alison M, Cuburu, Nicolas, Aublin, Anne, Maryanski, Janet L, Zuniga-Pflucker, Juan Carlos
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 01.05.2004
• Subjects: 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
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.172.9.5230

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.