DEFECTIVE T-CELL RECEPTOR SIGNALING AND CD8(+) THYMIC SELECTION IN HUMANS LACKING ZAP-70 KINASE

We have previously described a type of selective T cell deficiency (STD) characterized by persistent infections reminiscent of severe combined immunodeficiency. We show here that STD patients carry a mutation of zap-70, resulting in loss of the activity of this kinase. The thymi of zap-70(-/-) patients show the presence of CD4(+)CD8(+) cells in the cortex; however, only CD4, not CD8, single-positive cells are present in the medulla. Peripheral CD4(+) T cells from the zap 70(-/-) patients exhibit markedly reduced tyrosine phosphorylation, fail to produce interleukin-2, and do not proliferate in response to T cell receptor stimulation by mitogens or antigens. Thus, Zap-70 kinase appears to be indispensable for the development of CD8 single-positive T cells as well as for signal transduction and function of single-positive CD4 T cells.