| First Author | Ishikawa E | Year | 2010 |
| Journal | Proc Natl Acad Sci U S A | Volume | 107 |
| Issue | 46 | Pages | 19979-84 |
| PubMed ID | 21030681 | Mgi Jnum | J:166147 |
| Mgi Id | MGI:4839837 | Doi | 10.1073/pnas.1011228107 |
| Citation | Ishikawa E, et al. (2010) Germ-line elimination of electric charge on pre-T-cell receptor (TCR) impairs autonomous signaling for {beta}-selection and TCR repertoire formation. Proc Natl Acad Sci U S A 107(46):19979-84 |
| abstractText | 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-TCRalpha chain. To investigate the mechanism underlying this ligand-independent signaling in vivo, we established knock-in mice that express a pre-TCRalpha mutant lacking charged amino acids (D(22)R(24)R(102)R(117) to A(22)A(24)A(102)A(117); 4A). CD4(+)CD8(+) thymocyte number was significantly reduced in invariant pre-TCRalpha (pTalpha(4A/4A)) mice, whereas CD4(-)CD8(-) thymocytes were unaffected. The percentages of double-negative 3 (DN3) cells and gammadelta T cells were increased in the pTalpha(4A/4A) thymus, indicating that beta-selection is impaired in pTalpha(4A/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 pTalpha(4A/4A) cell surfaces than on those of the wild type, suggesting that the charged residues in pTalpha are critical for autonomous engagement and subsequent internalization of pre-TCR. Pre-TCR-mediated allelic exclusion of the TCRbeta gene was also inhibited in pTalpha(4A/4A) mice, and thereby, dual TCRbetas were expressed on pTalpha(4A/4A) T cells. Furthermore, the TCRbeta chain variable region (Vbeta) repertoire of mature T cells was significantly altered in pTalpha(4A/4A) mice. These results suggest that charged residues of pTalpha are critical for beta-selection, allelic exclusion, and TCRbeta repertoire formation. |
