Contributions of the T cell receptor-associated CD3gamma-ITAM to thymocyte selection
| Autor: | Helmut W. H. G. Kessels, Elsa Pépin, Stanley M. Belkowski, Jeroen H.N. van den Brakel, Ada M. Kruisbeek, Paul Krimpenfort, Mariëlle C. Haks, Sigrid A. A. Smeele |
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| Přispěvatelé: | Other departments |
| Jazyk: | angličtina |
| Rok vydání: | 2002 |
| Předmět: |
Antigens
Differentiation T-Lymphocyte CD3 Complex CD3γ–ITAM T-Lymphocytes Amino Acid Motifs Ligands TCR signaling Mice Negative selection Immunoreceptor tyrosine-based activation motif Immunology and Allergy Phosphorylation Cells Cultured ZAP-70 Protein-Tyrosine Kinase T cell activation ZAP70 Cell Differentiation Protein-Tyrosine Kinases Flow Cytometry medicine.anatomical_structure CD4 Antigens ITAM multiplicity Mitogen-Activated Protein Kinases Signal transduction Signal Transduction CD8 Antigens T cell CD3 Immunology Receptors Antigen T-Cell Linker for Activation of T cells chemical and pharmacologic phenomena Thymus Gland In Vitro Techniques Biology Article Antigens CD medicine Animals Lectins C-Type Crosses Genetic Adaptor Proteins Signal Transducing thymocyte selection T-cell receptor JNK Mitogen-Activated Protein Kinases Membrane Proteins Phosphoproteins Molecular biology Mice Mutant Strains Enzyme Activation Mutation biology.protein Carrier Proteins |
| Zdroj: | Journal of experimental medicine, 196(1), 1-13. Rockefeller University Press The Journal of Experimental Medicine |
| ISSN: | 0022-1007 |
| Popis: | The immunoreceptor tyrosine-based activation motifs (ITAMs) in the CD3 chains associated with the T cell receptor (TCR) are crucial for TCR signaling. To probe the role of the CD3gamma-ITAM in T cell development, we created knock-in mice in which the CD3gamma chain of the TCR complex is replaced by a mutant signaling-deficient CD3gamma chain, lacking the CD3gamma-ITAM. This mutation results in considerable impairment in positive selection in the polyclonal TCR repertoire. When CD3gamma-deltaITAM mice are crossed to mice expressing transgenic F5 TCRs, their thymocytes are completely unable to perform positive selection in vivo in response to intrathymic ligands. Also, the in vitro positive selection response of double-positive (DP) thymocytes with F5-CD3gamma-deltaITAM mutant receptors to their agonist ligand and many of its variants is severely impaired or abrogated. Yet, the binding and dissociation constants of agonist ligands for the F5 receptor are not affected by the CD3gamma-deltaITAM mutation. Furthermore, DP thymocytes with mutant receptors can respond to agonist ligand with normal antigen sensitivity and to normal levels, as shown by their ability to induce CD69 up-regulation, TCR down-regulation, negative selection, and ZAP70 and c-Jun NH2-terminal kinase activation. In sharp contrast, induction of extracellular signal-regulated kinase (ERK) activation and linker for activation of T cells (LAT) phosphorylation are severely impaired in these cells. Together, these findings underscore that intrinsic properties of the TCR-CD3 complex regulate selection at the DP checkpoint. More importantly, this analysis provides the first direct genetic evidence for a role of the CD3gamma-ITAM in TCR-driven thymocyte selection. |
| Databáze: | OpenAIRE |
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