Abstract
The size and sensitivity of the T-cell repertoire governs the effectiveness of immune responses against invading pathogens. Both are modulated by T-cell receptor (TCR) activity through molecular mechanisms, which remain unclear. Here, we provide genetic evidence that the SH2/SH3 domain containing proteins Nck lower the threshold of T-cell responsiveness. The hallmarks of Nck deletion were T-cell lymphopenia and hyporeactivity to TCR-mediated stimulation. In the absence of the Nck adaptors, peripheral T cells expressing a TCR with low avidity for self-antigens were strongly reduced, whereas an overall impairment of T-cell activation by weak antigenic stimulation was observed. Mechanistically, Nck deletion resulted in a significant decrease in calcium mobilization and ERK phosphorylation upon TCR engagement. Taken together, our findings unveil a crucial role for the Nck adaptors in shaping the T-cell repertoire to ensure maximal antigenic coverage and optimal T cell excitability.
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 / metabolism*
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Animals
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Blotting, Western
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Calcium / metabolism
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Cell Proliferation
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Cells, Cultured
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Dendritic Cells / cytology
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Dendritic Cells / metabolism
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Female
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Flow Cytometry
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Lymphopenia / genetics
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Lymphopenia / metabolism
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Lymphopenia / pathology
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Microscopy, Fluorescence
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / metabolism
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Oncogene Proteins / genetics
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Oncogene Proteins / metabolism*
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Phosphorylation
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Receptors, Antigen, T-Cell / genetics
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Receptors, Antigen, T-Cell / metabolism*
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Reverse Transcriptase Polymerase Chain Reaction
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T-Lymphocytes / cytology
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T-Lymphocytes / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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Nck protein
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Oncogene Proteins
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Receptors, Antigen, T-Cell
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Calcium