title: Human circulating CD4+CD25highFoxp3+ regulatory T cells kill autologous CD8+ but not CD4+ responder cells by Fas-mediated apoptosis.
abstract: Mechanisms utilized by human regulatory T cells (Treg) for elimination of effector cells may vary. We investigated the possibility that the mechanism of Treg suppression depends on Fas/FasL-mediated apoptosis of responder cells (RC). CD4(+)CD25(high)Foxp3(+) Treg and autologous CD4(+)CD25(-) and CD8(+)CD25(-) subsets of RC were isolated from blood of 25 cancer patients and 15 normal controls and cocultured in the presence of OKT3 and IL-2 (150 or 1000 IU/ml). Suppression of RC proliferation was measured in CFSE assays. RC and Treg apoptosis was monitored by 7-aminoactinomycin D staining in flow-based cytotoxicity assays. Treg from all subjects expressed CD95(+), but only Treg from cancer patients expressed CD95L. These Treg, when activated via TCR plus IL-2, up-regulated CD95 and CD95L expression (p < 0.001) and suppressed CD8(+) RC proliferation (p < 0.001) by inducing Fas-mediated apoptosis. However, Treg cocultured with CD4(+) RC suppressed proliferation independently of Fas/FasL. In cocultures, Treg were found to be resistant to apoptosis in the presence of 1000 IU/ml IL-2, but at lower IL-2 concentrations (150 IU/ml) they became susceptible to RC-induced death. Thus, Treg and RC can reciprocally regulate Treg survival, depending on IL-2 concentrations present in cocultures. This divergent IL-2-dependent resistance or sensitivity of Treg and RC to apoptosis is amplified in patients with cancer.
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Strauss
authors.forename: Christoph
authors.initials: C
authors.lastname: Bergmann
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Whiteside
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000276:immunology / Q000473:pathology; D049109:Cell Proliferation; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D053222:Fas Ligand Protein / Q000096:biosynthesis / Q000502:physiology; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000097:blood*; D006131:Growth Inhibitors / Q000097:blood / Q000502:physiology*; D006258:Head and Neck Neoplasms / Q000276:immunology / Q000473:pathology; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis / Q000097:blood*; D008297:Male; D008875:Middle Aged; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000096:biosynthesis / Q000502:physiology*
chemical_list: C418974:FOXP3 protein, human; D053222:Fas Ligand Protein; D051858:Forkhead Transcription Factors; D006131:Growth Inhibitors; D053645:Interleukin-2 Receptor alpha Subunit; D019014:fas Receptor