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* University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213;
Departments of Pathology, Immunology and Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232; and
Department of Otorhinolarnygology, University of Duisburg-Essen, Essen, Germany
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+CD25highFoxp3+ 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.
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1 Supported in part by National Institutes of Health Grants P01-CA109688, P01-DE12321, and R01-DE13918 to T.L.W. C.B. was supported by a grant from Philip Morris USA and Philip Morris International.
2 Address correspondence and reprint requests to Dr. Theresa L. Whiteside, University of Pittsburgh Cancer Institute, Research Pavilion at the Hillman Cancer Center, 5117 Centre Avenue, Suite 1.27, Pittsburgh, PA 15213-1863. E-mail address: whitesidetl{at}upmc.edu
3 Abbreviations used in this paper: Treg, regulatory T cells; RC, responder cells; AICD, activation-induced cell death; NC, normal controls; HNSCC, head and neck squamous cell carcinoma; AnxV, annexin V; FLOCA, flow-cytometry cytotoxicity assay; 7-AAD, 7 aminoactinomycin D; Tw, transwell insert.
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