Germ-line elimination of electric charge on pre-T-cell receptor (TCR) impairs autonomous signaling for beta-selection and TCR repertoire formation.

ABSTRACT: 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-TCR? chain. To investigate the mechanism underlying this ligand-independent signaling in vivo, we established knock-in mice that express a pre-TCR? 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-TCR? (pT?(4A/4A)) mice, whereas CD4(-)CD8(-) thymocytes were unaffected. The percentages of double-negative 3 (DN3) cells and ?? T cells were increased in the pT?(4A/4A) thymus, indicating that ?-selection is impaired in pT?(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 pT?(4A/4A) cell surfaces than on those of the wild type, suggesting that the charged residues in pT? are critical for autonomous engagement and subsequent internalization of pre-TCR. Pre-TCR-mediated allelic exclusion of the TCR? gene was also inhibited in pT?(4A/4A) mice, and thereby, dual TCR?s were expressed on pT?(4A/4A) T cells. Furthermore, the TCR? chain variable region (V?) repertoire of mature T cells was significantly altered in pT?(4A/4A) mice. These results suggest that charged residues of pT? are critical for ?-selection, allelic exclusion, and TCR? repertoire formation.

SUBMITTER: Ishikawa E 

PROVIDER: S-EPMC2993337 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature