Fluur, C. et al. Potential role for IL-7 in Fas-mediated T cell apoptosis during HIV infection. J. Immunol. 178, 5340-5350

Department of Microbiology and Tumor Biology Center, Karolinska Institutet, Stockholm, Sweden.
The Journal of Immunology (Impact Factor: 4.92). 04/2007; 178(8):5340-50. DOI: 10.4049/jimmunol.178.8.5340
Source: PubMed


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.

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Available from: Eva Rajnavolgyi
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    • "The IL-7Rα also plays an important role in signal transmission required for the development of the secondary lymphoid system [17]. At the same time it stimulates Fas antigen expression, by increasing T cell sensitivity to apoptosis [18]. "
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    • "IL-7 signaling is transmitted by a receptor composed by the IL-7Rα together with the common γ-chain, a subunit shared by several cytokines, including IL-2, IL-4, IL-7, IL-15 and IL-21. Since IL-2 and IL-15 share the ability of IL-7 to induce CD95 expression on resting T cells [9], we tested whether the different γ-chain using cytokines could induce IFN-γ production by T cells. T cells were cultured for five days in the presence of the above mentioned γ-chain using cytokines and the culture supernatant was tested for IFN-γ concentration. "
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    ABSTRACT: Interleukin-7 (IL-7) concentrations are increased in the blood of CD4+ T cell depleted individuals, including HIV-1 infected patients. High IL-7 levels might stimulate T cell activation and, as we have shown earlier, IL-7 can prime resting T cell to CD95 induced apoptosis as well. HIV-1 infection leads to B cell abnormalities including increased apoptosis via the CD95 (Fas) death receptor pathway and loss of memory B cells. Peripheral B cells are not sensitive for IL-7, due to the lack of IL-7Ra expression on their surface; however, here we demonstrate that high IL-7 concentration can prime resting B cells to CD95-mediated apoptosis via an indirect mechanism. T cells cultured with IL-7 induced high CD95 expression on resting B cells together with an increased sensitivity to CD95 mediated apoptosis. As the mediator molecule responsible for B cell priming to CD95 mediated apoptosis we identified the cytokine IFN-γ that T cells secreted in high amounts in response to IL-7. These results suggest that the lymphopenia induced cytokine IL-7 can contribute to the increased B cell apoptosis observed in HIV-1 infected individuals.
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    • "Briefly, IL-7 signaling triggers negative feedback to IL-7Rα transcription in order to prevent depletion by activated expanding cells, and ensure that IL-7 is available to other IL-7 dependent lymphocytes. The amounts of IL-7 available vary also depending on the clearance by the receptors present on lymphoid cells (Fluur et al., 2007). Therefore, in lymphopenic patients like that found early after bone marrow transplantation (BMT), blood levels of IL-7 are high. "
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