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* Department of Microbiology and Tumor Biology Center, Karolinska Institutet, Stockholm, Sweden;
Department of Drug Resistance and Evaluation, Istituto Superiore di Sanità, Rome, Italy;
Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892;
Department of Medicine, Infectious Diseases Unit, Karolinska University Hospital, Solna, Sweden;
¶ Institute of Immunology, Medical and Health Science Center, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
IL-7 promotes survival of resting T lymphocytes and induces T cell proliferation in lymphopenic conditions. As elevated IL-7 levels occur in HIV-infected individuals in addition to high Fas expression on T cells and increased sensitivity to Fas-induced apoptosis, we analyzed whether IL-7 has a regulatory role in Fas-mediated T cell apoptosis. We show that IL-7 up-regulates Fas expression on naive and memory T cells through a mechanism that involves translocation of Fas molecules from intracellular compartments to the cell membrane. IL-7 induced the association of Fas with the cytoskeletal component ezrin and a polarized Fas expression on the cell surface. The potential role of IL-7 in Fas up-regulation in vivo was verified in IL-7-treated macaques and in HIV-infected or chemotherapy treated patients by the correlation between serum IL-7 levels and Fas expression on T cells. IL-7 treatment primed T cells for Fas-induced apoptosis in vitro and serum IL-7 levels correlated with the sensitivity of T cells to Fas-induced apoptosis in HIV-infected individuals. Our data suggest an important role for IL-7 in Fas-mediated regulation of T cell homeostasis. Elevated IL-7 levels associated with lymphopenic conditions, including HIV-infection, might participate in the increased sensitivity of T cells for activation-induced apoptosis.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Swedish Medical Research Council, the Swedish International Development Cooperation Agency, Department of Research Cooperation, the Swedish Royal Academy of Science, the Division of Intramural Research Programs of the National Cancer Institute, National Institutes of Health, and the Hungarian National Research Fund (OTKA T043420). B.R. is supported by a European Community Marie Curie Training and Mobility Program Fellowship and by the Hungarian State Eotvos Fellowship. Angelo De Milito was supported by the fellowship of the Swedish Medical Research Council.
2 Address correspondence and reprint requests to Dr. Bence Rethi, Microbiology and Tumor Biology Center, Karolinska Institutet, Nobels väg 16, S-17177 Stockholm, Sweden. E-mail address: Bence.Rethi{at}ki.se
3 Abbreviations used in this paper: FasL, Fas ligand; FRET, fluorescence resonance energy transfer; MFI, mean fluorescence intensity.
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