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.
