Decreased zeta chain expression and apoptosis in CD3(+) peripheral blood Tlymphocytes of patients with melanoma

Expression of T-cell receptor- or Fc gamma receptor III-associated signal-t ransducing zeta chain is important for the functional integrity of immune c ells. We found that significantly higher proportions of circulating CD3(+) T cells as well as natural killer cells had low or absent expression of the zeta chain in patients with advanced melanoma than in normal donors (P < 0 ,0005), Decreased <zeta> expression was always observed in a small subset o f circulating CD3+ T cells that were in the process of apoptosis, i,e,, bou nd Annexin V or were terminal deoxynucleotidyl transferase-mediated nick en d labeling positive. Up to 80% of T cells in the peripheral blood of patien ts with melanoma were Fas(+), with the mean percentage of Fas(+)CD3(+) cell s significantly higher in patients (P < 0.004) than normal controls. These Fas(+)CD3(+) T cells were found to preferentially undergo apoptosis, Annexi n V binding, the loss of Fas expression from the cell surface as well as 5 down-regulation, which are associated with early apoptosis, were detected i n a proportion of circulating Fas(+)CD3(+). In Jurkat cells incubated with agonistic anti-Fas antibody (CH-11), a rapid loss of Fas expression from th e cell surface coincided with Annexin V binding and preceded the loss of 5 chain during early apoptosis, In a subset of Jurkat cells coincubated with human melanoma cells, Annexin V binding and 5 degradation as well as DNA fr agmentation were observed, indicating that the tumor induced T-cell death. Triggering of death receptors expressed on activated T lymphocytes was acco mpanied by the loss of 5 expression. On the other hand, soluble factors sec reted by melanoma cells induced down-regulation but no apoptosis in activat ed 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 susceptibi lity to apoptosis.