Nck adaptors are positive regulators of the size and sensitivity of the T-cell repertoire
Copyright policy )Nck adaptors are positive regulators of the size and sensitivity of the T-cell repertoire
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.
- University of Toronto Canada
- University of Queensland Australia
- Helmholtz Association of German Research Centres Germany
- University Hospital Ulm Germany
- University of Ulm Germany
Repertoire development, Male, 570, Blotting, Western, Receptors, Antigen, T-Cell, Signal transduction, Mice, Lymphopenia, T-cell activation, Animals, T-cell receptor, Phosphorylation, Cells, Cultured, Adaptor Proteins, Signal Transducing, Cell Proliferation, Mice, Knockout, Mitogen-Activated Protein Kinase 1, Oncogene Proteins, Mitogen-Activated Protein Kinase 3, Dendritic Cells, Flow Cytometry, Mice, Inbred C57BL, Microscopy, Fluorescence, Calcium, Female
Repertoire development, Male, 570, Blotting, Western, Receptors, Antigen, T-Cell, Signal transduction, Mice, Lymphopenia, T-cell activation, Animals, T-cell receptor, Phosphorylation, Cells, Cultured, Adaptor Proteins, Signal Transducing, Cell Proliferation, Mice, Knockout, Mitogen-Activated Protein Kinase 1, Oncogene Proteins, Mitogen-Activated Protein Kinase 3, Dendritic Cells, Flow Cytometry, Mice, Inbred C57BL, Microscopy, Fluorescence, Calcium, Female
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