A BLOCK IN BOTH EARLY T-LYMPHOCYTE AND NATURAL-KILLER-CELL DEVELOPMENT IN TRANSGENIC MICE WITH HIGH-COPY NUMBERS OF THE HUMAN CD3E GENE

A severe immunodeficiency involving a complete loss of T lymphocytes and natural killer cells was observed in independent lines of transgenic mice containing > 30 copies of the human CD3E gene (pL12). T-cell(-) natural killer (NK)(-) mice could also be generated by using a gene fragment pL12 Delta 1 (without exons 4A and 5) coding for the CD3-epsilon transmembrane region and its 55-amino acid nonenzymatic cytoplasmic tail. The abnormally small thymus gland in the homozygous transgenic animals, which was approximate to 1% the size of a wild-type thymus, contained only a few (2-4%) prethymocytes with a Thy-1(+)Pgp-1(+)IL-2R alpha(-)CD3(-)4(-)8(-) phenotype. In mice with lower copy numbers of the transgene thymocyte development was blocked at the Thy-1(+)Pgp-1(-)IL-2R alpha(+)CD3(-)4(-)8(-) stage, and normal NK activity was detected. Mice generated with high-copy numbers of a transgene pL12 Delta 2 (pL12 Delta 1 minus exons 6), coding for a truncated protein from which the CD3-epsilon extracellular domain, its transmembrane region, and most of its cytoplasmic region were absent, contained normal numbers of T lymphocytes and NK cells. These transgene effects suggested that recruitment of signal-transduction molecules by the cytoplasmic tail of this protein played an important role in the abrogation of both lineages. Taken together these observations support the notion that T lymphocytes and NK cells stemmed from a common precursor.