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Blood, 15 November 2006, Vol. 108, No. 10, pp. 3420-3427.
Prepublished online as a Blood First Edition Paper on August 3, 2006; DOI 10.1182/blood-2006-03-010850.
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Submitted March 21, 2006
Accepted July 9, 2006
Overlapping functions of human CD3 and mouse CD3 in  T cell development revealed in a humanized CD3 -deficient mouse
Edgar Fernandez-Malave*, Ninghai Wang, Manuel Pulgar, Wolfgang W Schamel, Balbino Alarcon, and Cox Terhorst
Centro de Biologia Molecular Severo Ochoa, Madrid, Spain
Beth Israel Deaconess Medical Center, Harvard Medical School
Max Planck-Institut fur Immunobiologie and University of Freiburg, Germany
* Corresponding author; email: efernandez{at}cbm.uam.es.
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 a 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 ndisplayed 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.

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