Functional Fas-ligand expression on T cells from HIV-1-infected patients is unrelated to CD4+ lymphopenia.
Recent studies have demonstrated that the expression of Fas by peripheral T cells from HIV-1+ patients is deregulated and increases the susceptibility of these cells to undergo apoptosis. Here, we show that secretion of Fas-ligand (L), the complementary agonist of Fas, is abnormally upregulated in CD4+ cells from HIV-1-infected individuals, particularly during the non-lymphopenic stages of the disease. An increase of soluble Fas-L occurred in T cell cultures from 26 patients with a number of CD4+ cells higher than 400/microliter, whereas it was almost undetectable in cultures from 21 severely lymphopenic patients (CD4+ < 200/microliter). The MTT test, cytofluorimetric analysis of cellular DNA, cytotoxicity, and proliferative assays using the Fas-transfected WC8 mouse lymphoma confirmed the cytocidal capability of T cell supernatants from non-lymphopenic patients. Double-fluorescence analysis revealed that the majority of CD4+ cells (approximately 90%) in these cultures secreted Fas-L in the presence of high intracellular gamma-interferon and low Bcl-2. In contrast, the CD8+/Fas-L+ population was comparably decreased (approximately 55%). Molecular cloning of Fas-L revealed a substantial expression of Fas-L mRNA in cells from non-lymphopenic patients compared with patients with advanced disease and healthy controls. Since CD4+ cells of Th1 phenotype are impaired during HIV-1 infection and show high cellular expression of Fas-L, it is conceivable that excess Fas-L during the early or non-lymphopenic phase of the disease increases the extent of apoptosis in these cells by the Fas/Fas-L pathway. The defective expression of the ligand in severely lymphopenic stages could be explained by exhaustion of this mechanism as the disease progresses.
Silvestris
F
F
Department of Biomedical Sciences and Human Oncology, University of Bari, Italy.
Cafforio
P
P
Camarda
G
G
Tucci
M
M
Frassanito
M A
MA
Dammacco
F
F
D017209:Apoptosis / Q000276:immunology; D015415:Biomarkers; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000166:cytology / Q000821:virology*; D017931:DNA Primers; D053222:Fas Ligand Protein; D005434:Flow Cytometry; D015870:Gene Expression / Q000276:immunology; D015658:HIV Infections / Q000276:immunology* / Q000378:metabolism; D015497:HIV-1; D006801:Humans; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000032:analysis; D016014:Linear Models; D008231:Lymphopenia / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D008562:Membrane Glycoproteins / Q000032:analysis / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D019014:fas Receptor / Q000032:analysis / Q000235:genetics
D015415:Biomarkers; D017931:DNA Primers; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D019014:fas Receptor; D007371:Interferon-gamma