Overlapping functions of human CD3 and mouse CD3 in T-cell development revealed in a humanized CD3 -deficient mouse
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چکیده
Humans lacking the CD3 subunit of the pre-TCR and TCR complexes exhibit a mild T lymphopenia, but have normal T cells. By contrast, CD3 -deficient mice are almost devoid of mature T cells due to an early block of intrathymic development at the CD4 CD8 double-negative (DN) stage. This suggests that in humans but not in mice, the highly related CD3 chain replaces CD3 during T-cell development. To determine whether human CD3 (hCD3 ) functions in a similar manner in the mouse in the absence of CD3 , we introduced an hCD3 transgene in mice that were deficient for both CD3 and CD3 , in which thymocyte development is completely arrested at the DN stage. Expression of hCD3 efficiently supported pre-TCR– mediated progression from the DN to the CD4 CD8 double-positive (DP) stage. However, TCR-mediated positive and negative thymocyte selection was less efficient than in wild-type mice, which correlated with a marked attenuation of TCR-mediated signaling. Of note, murine CD3 -deficient TCR complexes that had incorporated hCD3 displayed abnormalities in structural stability resembling those of T cells from CD3 -deficient humans. Taken together, these data demonstrate that CD3 and CD3 play a different role in humans and mice in pre-TCR and TCR function during T-cell development. (Blood. 2006;108:3420-3427)
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تاریخ انتشار 2006