ABSENCE OF ZAP-70 PREVENTS SIGNALING THROUGH THE ANTIGEN RECEPTOR ON PERIPHERAL-BLOOD T-CELLS BUT NOT ON THYMOCYTES

Recently, a severe combined immunodeficiency syndrome with a deficienc y of CD8(+) peripheral T cells and a TCR signal transduction defect in peripheral CD4(+) T cells was associated with mutations in ZAP-70. Si nce TCR signaling is required in developmental decisions resulting in mature CD4 (and CD8) T cells, the presence of peripheral CD4(+) T cell s expressing TCRs incapable of signaling in these patients is paradoxi cal. Here, we show that the TCRs on thymocytes, but not peripheral T c ells, from a ZAP 70-deficient patient are capable of signaling. Moreov er, the TCR on a thymocyte line derived from this patient can signal, and the homologous kinase Syk is present at high levels and is tyrosin e phosphorylated after TCR stimulation. Thus, Syk may compensate for t he loss of ZAP-70 and account for the thymic selection of at least a s ubset of T cells (CD4(+)) in ZAP-70-deficient patients.