CD8 LYMPHOCYTOPENIA CAUSED BY ZAP-70 DEFICIENCY

ZAP-70 is a member of a distinct family of cytoplasmic tyrosine kinases involved in signal transduction from the antigen receptors. The family currently consists of ZAP-70, which is found in T lymphocytes and natural killer (NK) cells and Syk, which is most highly expressed in B lymphocytes and platelets. 12 ZAP-70 was isolated initially as an ATP-binding phosphoprotein associating with a component of the T-cell receptor (TCR) signaling complex, CD3ζ, after TCR stimulation. 9,87,90 ZAP-70 has a single protein tyrosine kinase catalytic domain and tandem SH2 domains responsible for binding to the CD3ζ receptor chain. This structure is shared by the closely related Syk kinase. 12 Both kinases also have multiple tyrosine residues predicted to form recognition sites for SH2 domains. ZAP-70 is expressed from an extremely early point in T-cell differentiation, and is present in all the major thymocyte subpopulations. 11 Expression does not seem to be inducible, but remains constant throughout the developmental process. A single gene on chromosome 2q12 encodes the human ZAP-70 kinase. 38 Although playing a critical role in T-cell antigen receptor signaling, the activation of ZAP-70 is not the primary event following TCR ligation. Rather, ZAP-70 activation seems to lie downstream of members of the src tyrosine kinase family, and, as a result of their activity, ZAP-70 is activated. 82,89 This is, in part, because of phosphorylation of CD3ζ by the src kinases, primarily p56lck, and, in part, because of phosphorylation of ZAP-70 itself. On TCR stimulation, ZAP-70 rapidly moves from the cytoplasm to the plasma membrane, binding to the CD3ζ chain of the TCR complex. It then is tyrosine phosphorylated rapidly and its kinase domain is activated. Various signal transduction proteins become associated with ZAP-70, some of which are substrates for its kinase domain and others that modify and regulate its activity. Localization to the plasma membrane plays an important role in ZAP-70 activation, as artificial targeting to the membrane results in ZAP-70 phosphorylation and activation of the downstream ras/MAPK and Ca 2+ /calcineurin pathways. 25