Overlapping functions of human CD3delta and mouse CD3gamma in alphabeta T-cell development revealed in a humanized CD3gamma-mouse

Humans lacking the CD3gamma subunit of the pre-TCR and TCR complexes exhibit a mild alphabeta T lymphopenia, but have normal T cells. By contrast, CD3gamma-deficient mice are almost devoid of mature alphabeta 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 CD3delta chain replaces CD3gamma during alphabeta T-cell development. To determine whether human CD3delta (hCD3delta) functions in a similar manner in the mouse in the absence of CD3gamma, we introduced an hCD3delta transgene in mice that were deficient for both CD3delta and CD3gamma, in which thymocyte development is completely arrested at the DN stage. Expression of hCD3delta efficiently supported pre-TCR-mediated progression from the DN to the CD4(+)CD8(+) double-positive (DP) stage. However, alphabetaTCR-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 CD3gamma-deficient TCR complexes that had incorporated hCD3delta displayed abnormalities in structural stability resembling those of T cells from CD3gamma-deficient humans. Taken together, these data demonstrate that CD3delta and CD3gamma play a different role in humans and mice in pre-TCR and TCR function during alphabeta T-cell development.