Decreased zeta chain expression and apoptosis in CD3+ peripheral blood T lymphocytes of patients with melanoma.
Expression of T-cell receptor- or Fcgamma receptor III-associated signal-transducing zeta 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 zeta chain in patients with advanced melanoma than in normal donors (P < 0.0005). Decreased zeta 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 zeta 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 zeta chain during early apoptosis. In a subset of Jurkat cells coincubated with human melanoma cells, Annexin V binding and zeta 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 zeta 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.
Dworacki
G
G
Department of Pathology, University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute, Pennsylvania 15213-2582, USA.
Meidenbauer
N
N
Kuss
I
I
Hoffmann
T K
TK
Gooding
W
W
Lotze
M
M
Whiteside
T L
TL
D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis; D017252:CD3 Complex / Q000096:biosynthesis*; D015704:CD4 Antigens / Q000096:biosynthesis; D019002:CD56 Antigen / Q000096:biosynthesis; D016827:CD8 Antigens / Q000096:biosynthesis; D018920:Coculture Techniques; D053938:DNA Fragmentation; D015536:Down-Regulation; D005434:Flow Cytometry; D006801:Humans; D020287:In Situ Nick-End Labeling; D019169:Jurkat Cells; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008545:Melanoma / Q000097:blood* / Q000378:metabolism / Q000473:pathology*; D008565:Membrane Proteins / Q000096:biosynthesis*; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism*; D013997:Time Factors; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D019014:fas Receptor / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism
D017304:Annexin A5; D017252:CD3 Complex; D015704:CD4 Antigens; D019002:CD56 Antigen; D016827:CD8 Antigens; D008565:Membrane Proteins; D011948:Receptors, Antigen, T-Cell; C054979:antigen T cell receptor, zeta chain; D019014:fas Receptor