In vivo apoptosis of CD8(+) lymphocytes in acute myeloid leukemia patients: involvement of soluble HLA-I and Fas ligand.
In this study, we show that high serum levels of soluble human leukocyte antigens (HLA) class I molecules (sHLA-I, range: 0.7-1.7 micro g/ml) and soluble Fas ligand (FasL, range: 0.4-1.9 ng/ml) are detected in patients with acute myeloid leukemia (AML) at diagnosis, compared with healthy donors (HD) (sHLA-I, range: 0.1-0.6 micro g/ml; sFasL, range: 0.1-0.4 ng/ml). Patients' sera were able to induce transcription and secretion of FasL in CD8(+) T cells, followed by apoptosis in vitro; this apoptosis was inhibited by anti-HLA-I-specific monoclonal antibodies, suggesting that sHLA-I is responsible for cell death. These findings closely relate to the in vivo upregulation of FasL transcription observed in peripheral blood (PB) lymphocytes from AML patients; in the same cells, mRNA for the antiapoptotic proteins Bcl-2 and Bcl-x(L) was downregulated. Interestingly, caspase-8 and caspase-3, both downstream mediators of death receptor-induced apoptosis, were activated in CD8(+) cells of AML patients; one-third of these cells were already apoptotic in vivo, at variance with lymphocytes of HD. These data strongly suggest that in AML, increased levels of sHLA-I molecules may contribute to the elimination of potentially anti-tumor effector cells through a FasL/Fas interaction.
Contini
P
P
Laboratory of Immunology, University of Genoa, Genoa, Italy.
Zocchi
M R
MR
Pierri
I
I
Albarello
A
A
Poggi
A
A
D000208:Acute Disease; D000328:Adult; D000368:Aged; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D053222:Fas Ligand Protein / Q000276:immunology*; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D007951:Leukemia, Myeloid / Q000145:classification / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D014635:Valproic Acid / Q000627:therapeutic use
D004791:Enzyme Inhibitors; D053222:Fas Ligand Protein; D015395:Histocompatibility Antigens Class I; D056572:Histone Deacetylase Inhibitors; D014635:Valproic Acid