title: Human T-cell leukemia virus type 2 induces survival and proliferation of CD34(+) TF-1 cells through activation of STAT1 and STAT5 by secretion of interferon-gamma and granulocyte macrophage-colony-stimulating factor.
abstract: Human T-cell leukemia-lymphoma virus (HTLV) type-2 can induce the survival and proliferation of CD34(+) TF-1 cells deprived of interleukin (IL)-3. This effect did not require productive infection and occurred when HTLV-2 was produced from T cells (CMo), but not from B cells (BMo), unless the latter virus was complexed with anti-HLA-DR monoclonal antibodies (mAbs). Cellular and molecular mechanisms triggered by HTLV-2 interaction with TF-1 cells were here investigated. Activation of signal transducer and activator of transcription (STAT) 5 protein occurred in TF-1 cells incubated either with IL-3 or with HTLV-2/CMo; in addition the virus, but not IL-3, activated STAT1. The effect of HTLV-2 required several hours, suggesting dependence on the induction of cellular factors. By screening a panel of secreted factors, granulocyte macrophage-colony-stimulating factor (GM-CSF), interferon (IFN)-gamma, and stem cell factor (SCF) were found induced by HTLV-2 in TF-1 cells. Of note is the fact that these molecules induce a variety of biologic effects through the activation of STAT proteins, including STAT1 and STAT5. Neutralization experiments indicated that GM-CSF and IFN-gamma, but not SCF, were responsible for HTLV-2-induced STAT activation, whereas anti-GM-CSF antibodies greatly inhibited TF-1 cell proliferation. Finally, incubation of BMo virus with anti-HLA-DR mAb rescued TF-1 cell survival in the absence of IL-3. Thus, HTLV-2 interaction with CD34(+) precursor cells may lead to the expression of cytokines that, by inducing autocrine activation of STATs, may influence the host's regenerative capacity and immune response to HTLV-2 and to other infectious agents.
authors.affiliation: AIDS Immunopathogenesis Unit, San Raffaele Scientific Institute, Milan, Italy. c.bovolenta@hsr.it
authors.forename: Chiara
authors.initials: C
authors.lastname: Bovolenta
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Pilotti
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Mauri
authors.forename: Marco
authors.initials: M
authors.lastname: Turci
authors.forename: Paolo
authors.initials: P
authors.lastname: Ciancianaini
authors.forename: Paola
authors.initials: P
authors.lastname: Fisicaro
authors.forename: Umberto
authors.initials: U
authors.lastname: Bertazzoni
authors.forename: Guido
authors.initials: G
authors.lastname: Poli
authors.forename: Claudio
authors.initials: C
authors.lastname: Casoli
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D018952:Antigens, CD34 / Q000032:analysis; D001402:B-Lymphocytes / Q000821:virology; D002454:Cell Differentiation; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000502:physiology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006684:HLA-DR Antigens / Q000276:immunology; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D015367:Human T-lymphotropic virus 2 / Q000276:immunology / Q000502:physiology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007377:Interleukin-3 / Q000494:pharmacology; D004915:Leukemia, Erythroblastic, Acute; D008894:Milk Proteins; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D050794:STAT1 Transcription Factor; D050799:STAT5 Transcription Factor; D019089:Stem Cell Factor / Q000378:metabolism; D013601:T-Lymphocytes / Q000821:virology; D015534:Trans-Activators / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D018952:Antigens, CD34; D004268:DNA-Binding Proteins; D006684:HLA-DR Antigens; D007377:Interleukin-3; D008894:Milk Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050799:STAT5 Transcription Factor; D019089:Stem Cell Factor; D015534:Trans-Activators; D019000:Phosphotyrosine; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor