The pre-T-cell receptor (TCR) is crucial for the early T-cell development, but the ligand for pre-TCR remains unidentified. We recently proposed a model that pre-TCR complexes oligomerize spontaneously through interactions of the pre-TCRα chain. To investigate the mechanism underlying this ligand-independent signaling in vivo, we established knock-in mice that express a pre-TCRα mutant lacking charged amino acids (D22R 24R102R117 to A22A 24A102A117; 4A). CD4+CD8+ thymocyte number was significantly reduced in invariant pre-TCRα (pTα4A/4A) mice, whereas CD4-CD8- thymocytes were unaffected. The percentages of double-negative 3 (DN3) cells and γδ T cells were increased in the pTα4A/4A thymus, indicating that p-selection is impaired in pTα4A/4A mice. Pre-TCR-mediated tyro- sine phosphorylation and clonal expansion into double-positive thy- mocytes were also defective in the knock-in mice. Pre-TCR was expressed at higher levels on pTα4A/4A cell surfaces than on those of the wild type, suggesting that the charged residues in pTa are critical for autonomous engagement and subsequent internalization of pre-TCR. Pre-TCR-mediated allelic exclusion of the TCRβ gene was also inhibited in pTα4A/4A mice, and thereby, dual TCRβs were expressed on pTα4A/4A T cells. Furthermore, the TCRβ chain variable region (Vβ) repertoire of mature T cells was significantly alteredinpTα4A/4A mice. These results suggest that charged residues of pTα are critical for p-selection, allelic exclusion, and TCRβ repertoire formation.
|Number of pages||6|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|Publication status||Published - Nov 16 2010|
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