Article: article from journal or magazin.
Allelic exclusion of the TCR alpha-chain is an active process requiring TCR-mediated signaling and c-Cbl.
Journal of Immunology
Publication types: Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.Publication Status: ppublish
Phenotypic allelic exclusion at the TCRalpha locus is developmentally regulated in thymocytes. Many immature thymocytes express two cell surface alpha-chain species. Following positive selection, the vast majority of mature thymocytes and peripheral T cells display a single cell surface alpha-chain. A posttranslational mechanism occurring at the same time as positive selection and TCR up-regulation leads to this phenotypic allelic exclusion. Different models have been proposed to explain the posttranslational regulation of the alpha-chain allelic exclusion. In this study, we report that allelic exclusion is not regulated by competition between distinct alpha-chains for a single beta-chain, as proposed by the dueling alpha-chain model, nor by limiting CD3 zeta-chain in mature TCR(high) thymocytes. Our data instead favor the selective retention model where the positive selection signal through the TCR leads to phenotypic allelic exclusion by specifically maintaining cell surface expression of the selected alpha-chain while the nonselected alpha-chain is internalized. The use of inhibitors specific for Lck and/or other Src kinases indicates a role for these protein tyrosine kinases in the signaling events leading to the down-regulation of the nonselectable alpha-chain. Loss of the ubiquitin ligase/TCR signaling adapter molecule c-Cbl, which is important in TCR down-modulation and is a negative regulator of T cell signaling, leads to increased dual alpha-chain expression on the cell surface of double-positive thymocytes. Thus, not only is there an important role for TCR signaling in causing alpha-chain allelic exclusion, but differential ubiquitination by c-Cbl may be an important factor in causing only the nonselected alpha-chain to be down-modulated.
Alleles, Animals, Antibody Affinity/genetics, Binding, Competitive/genetics, Binding, Competitive/immunology, Cross-Linking Reagents/metabolism, Dimethyl Sulfoxide/pharmacology, Down-Regulation/drug effects, Down-Regulation/genetics, Fetus, Gene Expression Regulation/drug effects, Gene Expression Regulation/immunology, Genes, T-Cell Receptor alpha, Genes, T-Cell Receptor beta, Immune Sera/metabolism, Immunophenotyping, Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/antagonists & inhibitors, Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/biosynthesis, Membrane Proteins/biosynthesis, Membrane Proteins/genetics, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Mutant Strains, Mice, Transgenic, Organ Culture Techniques, Proto-Oncogene Proteins/deficiency, Proto-Oncogene Proteins/genetics, Proto-Oncogene Proteins c-cbl, Pyrazoles/pharmacology, Pyrimidines/pharmacology, Receptors, Antigen, T-Cell/biosynthesis, Receptors, Antigen, T-Cell/genetics, Receptors, Antigen, T-Cell, alpha-beta/antagonists & inhibitors, Receptors, Antigen, T-Cell, alpha-beta/biosynthesis, Signal Transduction/drug effects, Signal Transduction/genetics, Thymus Gland/cytology, Thymus Gland/immunology, Ubiquitin-Protein Ligases
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