ZAP70

The T cell receptor has no innate enzymatic activity. Due to this, T cell receptors rely on signaling molecules to transduce a signal from the cell membrane. ZAP-70 is a critical cytoplasmic tyrosine kinase that initiates a signal pathway downstream of an activated T cell receptor.^[8]

T lymphocytes are activated by engagement of the T cell receptor with processed antigen fragments presented by professional antigen presenting cells (i.e. macrophages, dendritic cells, Langerhans cells and B cells) via the MHC. Upon this activation, the TCR co-receptor CD4 (expressed on T helper cells) or CD8 (expressed on cytotoxic T cells) binds to the MHC, activating the co-receptor associated tyrosine kinase Lck. Lck is moved near the CD3 complex and phosphorylates the tyrosines in the immunoreceptor tyrosine-based activation motifs (ITAMS), creating a docking site for ZAP-70.^[9] The most important member of the CD3 family is CD3-zeta, to which ZAP-70 binds (hence the abbreviation). The tandem SH2-domains of ZAP-70 are engaged by the doubly phosphorylated ITAMs of CD3-zeta, which positions ZAP-70 to phosphorylate the transmembrane protein linker for activation of T cells (LAT).^[9] Phosphorylated LAT, in turn, serves as a docking site to which a number of signaling proteins bind, including the SH2-domain-containing leukocyte protein of 76 kDa (SLP-76).^[9] SLP-76 is also phosphorylated by ZAP-70, which requires its activation by Src family kinases.^[10] The final outcome of T cell activation is the transcription of several gene products which allow the T cells to differentiate, proliferate, and secrete a number of cytokines.

Due to its role in lymphocyte signaling, ZAP-70 has been associated with several diseases affecting lymphocytes. ZAP-70 expression is a significant indicator of the survival of lymphocytes and has been notably associated with chronic lymphocytic leukemia (CLL).^[11] CLL is a cancer that develops from overproduction of B cells in the bone marrow.

In people with CLL, higher levels of ZAP-70 confers a worse prognosis; CLL patients that are positive for the marker ZAP-70 have an average survival of 8 years, whereas those that are negative for ZAP-70 have an average survival of more than 25 years. Many patients, especially older ones, with slowly progressing disease can be reassured and may not need any treatment in their lifetimes.^[12] In individuals with CLL, higher levels of ZAP-70 is associated with a higher number of malignant B cells activated.^[5] Increased expression of ZAP-70 in B cell malignancies is correlated with increased association between malignant B cells and the immune environment, suggesting a complex role for ZAP-70 in B cell signaling.^[5]

In systemic lupus erythematosus, the Zap-70 receptor pathway is missing and the homolog Syk takes its place.^[13]

ZAP-70 deficiency results in a form of autosomal recessive immune deficiency named combined immunodeficiency.^[14] Patients afflicted with combined immunodeficiency have a normal lymphocyte count, but they have low concentrations of T helper cells and cytotoxic T cells.^[14] Patients were also found to have irregular lymphocyte proliferation responses.^[14] These effects suggest that a deficiency in ZAP-70 results in decreased rates of T cell activation and subsequent signal transductions.^[14]

ZAP-70 has been shown to interact with:

• Lck
• Syk
• T cell receptor
• Chronic lymphocytic leukemia
• Combined immunodeficiency