Absence o f Z A P - 7 0 Prevents Signal ing through the Ant igen

Recently, a severe combined immunodeficiency syndrome with a deficiency of CD8 + peripheral T cells and a T C R signal transduction defect in peripheral CD4 + T cells was associated with mutations in ZAP-70. Since T C R signaling is required in developmental decisions resulting in mature CD4 (and CD8) T cells, the presence of peripheral CD4 + T cells expressing TCRs incapable of signaling in these patients is paradoxical. Here, we show that the TCRs on thymocytes, but not peripheral T cells, from a ZAP-70-deficient patient are capable of signaling. Moreover, the T C R on a thymocyte line derived from this patient can signal, and the homologous kinase Syk is present at high levels and is tyrosine phosphorylated after T C R stimulation. Thus, Syk may compensate for the loss of ZAP-70 and account for the thymic selection of at least a subset o f T cells (CD4 +) in ZAP-70-deficient patients.