Abstract
Thymic selection shapes the T cell repertoire to ensure maximal antigenic coverage against pathogens while preventing autoimmunity. Recognition of self-peptides in the context of peptide-MHC complexes by the TCR is central to this process, which remains partially understood at the molecular level. In this study we provide genetic evidence that the Nck adapter proteins are essential for thymic selection. In vivo Nck deletion resulted in a reduction of the thymic cellularity, defective positive selection of low-avidity T cells, and impaired deletion of thymocytes engaged by low-potency stimuli. Nck-deficient thymocytes were characterized by reduced ERK activation, particularly pronounced in mature single positive thymocytes. Taken together, our findings identify a crucial role for the Nck adapters in enhancing TCR signal strength, thereby fine-tuning the threshold of thymocyte selection and shaping the preimmune T cell repertoire.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / immunology*
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Enzyme Activation / genetics
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Enzyme Activation / immunology
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Extracellular Signal-Regulated MAP Kinases / genetics
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Extracellular Signal-Regulated MAP Kinases / immunology
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Gene Deletion
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Histocompatibility Antigens / genetics
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Histocompatibility Antigens / immunology
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Histocompatibility Antigens / metabolism
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Mice
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Mice, Knockout
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Oncogene Proteins / genetics
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Oncogene Proteins / immunology*
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Oncogene Proteins / metabolism
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Peptides / genetics
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Peptides / immunology
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Peptides / metabolism
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Receptors, Antigen, T-Cell / genetics
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Receptors, Antigen, T-Cell / immunology*
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Receptors, Antigen, T-Cell / metabolism
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Signal Transduction / genetics
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Signal Transduction / immunology*
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T-Lymphocytes / cytology
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T-Lymphocytes / immunology*
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T-Lymphocytes / metabolism
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Thymus Gland / cytology
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Thymus Gland / immunology*
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Thymus Gland / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Histocompatibility Antigens
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Nck protein
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Oncogene Proteins
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Peptides
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Receptors, Antigen, T-Cell
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Extracellular Signal-Regulated MAP Kinases