Germ-line elimination of electric charge on pre-T-cell receptor (TCR) impairs autonomous signaling for β-selection and TCR repertoire formation
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-in...
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Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2010-11, Vol.107 (46), p.19979-19984 |
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Zusammenfassung: | 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 (D²²R²⁴R¹⁰²R¹¹⁷ to A²²A²⁴A¹⁰²A¹¹⁷; 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 β-selection is impaired in pTα⁴A/⁴A mice. Pre-TCR-mediated tyrosine phosphorylation and clonal expansion into double-positive thymocytes 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 pTα 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 altered in pTα⁴A/⁴A mice. These results suggest that charged residues of pTα are critical for β-selection, allelic exclusion, and TCRβ repertoire formation. |
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ISSN: | 0027-8424 1091-6490 |
DOI: | 10.1073/pnas.1011228107 |