title: Interferon-α inhibits CD4 T cell responses to interleukin-7 and interleukin-2 and selectively interferes with Akt signaling.
abstract: Persistent type I IFN production occurs during chronic viral infections, such as HIV disease. As type I IFNs have antiproliferative activity, it is possible that chronic exposure to these cytokines could adversely affect T cell homeostasis. We investigated the capacity of IFN-α to impair T cell proliferation induced by the homeostatic cytokine, IL-7, or another common γ-chain cytokine, IL-2, in cells from healthy human donors. We found that IL-7- or IL-2-induced proliferation of CD4(+) T cells was partially inhibited in the presence of IFN-α. The CD4(+) T cells that were exposed to IFN-α also displayed attenuated induction of IL-2 and CD40L following TCR stimulation. Analyses of signaling pathways indicated that IL-7 and IL-2 induced a delayed and sustained P-Akt signal that lasted for several days and was partially inhibited by IFN-α. In contrast, IL-7-induced P-STAT5 was not affected by IFN-α. Furthermore, IFN-α had no detectable effect on P-Akt that was induced by the chemokine SDF-1. Both inhibitors of P-Akt and P-STAT5 blocked IL-7-induced T cell proliferation, confirming that both signaling pathways are important for IL-7-induced T cell proliferation. These results demonstrate that IFN-α can selectively inhibit cytokine-induced P-Akt as a potential mechanism to disrupt homeostasis of T lymphocytes.
authors.affiliation: Departments of *Medicine, Division of Infectious Diseases and HIV Medicine, and Pathology, Center for AIDS Research, Case Western Reserve University/University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Thao P
authors.initials: TP
authors.lastname: Nguyen
authors.affiliation: Departments of *Medicine, Division of Infectious Diseases and HIV Medicine, and Pathology, Center for AIDS Research, Case Western Reserve University/University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Doug A
authors.initials: DA
authors.lastname: Bazdar
authors.affiliation: Departments of *Medicine, Division of Infectious Diseases and HIV Medicine, and Pathology, Center for AIDS Research, Case Western Reserve University/University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Mudd
authors.affiliation: Departments of *Medicine, Division of Infectious Diseases and HIV Medicine, and Pathology, Center for AIDS Research, Case Western Reserve University/University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Lederman
authors.affiliation: Departments of *Medicine, Division of Infectious Diseases and HIV Medicine, and Pathology, Center for AIDS Research, Case Western Reserve University/University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Clifford V
authors.initials: CV
authors.lastname: Harding
authors.affiliation: Departments of *Medicine, Division of Infectious Diseases and HIV Medicine, and Pathology, Center for AIDS Research, Case Western Reserve University/University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Gareth A
authors.initials: GA
authors.lastname: Hardy
authors.affiliation: Departments of *Medicine, Division of Infectious Diseases and HIV Medicine, and Pathology, Center for AIDS Research, Case Western Reserve University/University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, Ohio, USA sfs2@case.edu.
authors.forename: Scott F
authors.initials: SF
authors.lastname: Sieg
mesh_terms: D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D023201:CD40 Ligand / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D005786:Gene Expression Regulation; D006801:Humans; D016898:Interferon-alpha / Q000276:immunology* / Q000494:pharmacology; D007376:Interleukin-2 / Q000276:immunology* / Q000494:pharmacology; D015851:Interleukin-7 / Q000276:immunology* / Q000494:pharmacology; D010766:Phosphorylation; D061251:Primary Cell Culture; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction
chemical_list: D015704:CD4 Antigens; C508605:IL7 protein, human; D016898:Interferon-alpha; D007376:Interleukin-2; D015851:Interleukin-7; D011948:Receptors, Antigen, T-Cell; D050799:STAT5 Transcription Factor; D023201:CD40 Ligand; D051057:Proto-Oncogene Proteins c-akt
keywords: cytokines; homeostatic proliferation