A homozygous mutation in the kinase domain of ZAP-70, a T cell recepto
r-associated protein tyrosine kinase, produced a distinctive form of h
uman severe combined immunodeficiency. Manifestations of this disorder
included profound immunodeficiency, absence of peripheral CD8(+) T ce
lls, and abundant peripheral CD4(+) T cells that were refractory to T
cell receptor-mediated activation. These findings demonstrate that ZAP
-70 is essential for human T cell function and suggest that CD4(+) and
CD8(+) T cells depend on different intracellular signaling pathways t
o support their development or survival.