Decreased ζ Chain Expression and Apoptosis in CD3+ Peripheral Blood T Lymphocytes of Patients with Melanoma

Expression of T-cell receptor- or Fc γ receptor III-associated signal-transducing ζ chain is important for the functional integrity of immune cells. We found that significantly higher proportions of circulating CD3 + T cells as well as natural killer cells had low or absent expression of the ζ chain in patients with advanced melanoma than in normal donors ( P < 0.0005). Decreased ζ expression was always observed in a small subset of circulating CD3 + T cells that were in the process of apoptosis, i.e., bound Annexin V or were terminal deoxynucleotidyl transferase-mediated nick end labeling positive. Up to 80% of T cells in the peripheral blood of patients with melanoma were Fas + , with the mean percentage of Fas + CD3 + cells significantly higher in patients ( P < 0.004) than normal controls. These Fas + CD3 + T cells were found to preferentially undergo apoptosis. Annexin V binding, the loss of Fas expression from the cell surface as well as ζ, down-regulation, which are associated with early apoptosis, were detected in a proportion of circulating Fas + CD3 + . In Jurkat cells incubated with agonistic anti-Fas antibody (CH-11), a rapid loss of Fas expression from the cell surface coincided with Annexin V binding and preceded the loss of ζ chain during early apoptosis. In a subset of Jurkat cells coincubated with human melanoma cells, Annexin V binding and ζ degradation as well as DNA fragmentation were observed, indicating that the tumor induced T-cell death. Triggering of death receptors expressed on activated T lymphocytes was accompanied by the loss of ζ expression. On the other hand, soluble factors secreted by melanoma cells induced down-regulation but no apoptosis in activated normal T cells. In the circulation of patients with melanoma, apoptosis of immune effector cells may be related to the state of chronic activation, resulting in the up-regulation of death receptors and increased susceptibility to apoptosis.