title: Chronic exposure to IFNα drives medullar lymphopoiesis towards T-cell differentiation in mice.
abstract: Interferon-α is a potent antiviral agent and a vigorous adjuvant in the induction of T-cell responses but its use is limited by hematologic toxicity. Interferon-α alters hematopoietic stem cell dormancy and impairs myelocytic and erythrocytic/megakaryocytic differentiation from hematopoietic progenitors. However, the effect of chronic interferon-α exposure on hematopoietic precursors has still not been well characterized. Here, we transduced the liver of mice with an adenoassociated vector encoding interferon-α to achieve sustained high serum levels of the cytokine. The bone marrow of these animals showed diminished long-term and short-term hematopoietic stem cells, reduction of multipotent progenitor cells, and marked decrease of B cells, but significant increase in the proportion of CD8(+) and CD4(+)CD8(+) T cells. Upon adoptive transfer to RAG(-/-) mice, bone marrow cells from interferon-α-treated animals generated CD4(+) and CD8(+) T cells while CD19(+), CD11b(+) and NK1.1(+) lineages failed to develop. These effects are associated with the transcriptional downregulation of transcription factors involved in B-cell differentiation and modulation of key factors for T-cell development. Thus, sustained interferon-α exposure causes hematopoietic stem cells exhaustion and drives common lymphoid progenitors towards T-cell generation.
authors.affiliation: Division of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Marianna
authors.initials: M
authors.lastname: Di Scala
authors.affiliation: Division of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Gil-Fariña
authors.affiliation: Division of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Lucia
authors.initials: L
authors.lastname: Vanrell
authors.affiliation: Division of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Sánchez-Bayona
authors.affiliation: Department of Instrumental Techniques-Cytometry Unit, Center for Applied Medical Research, University of Navarra, Pamplona, Spain.
authors.forename: Diego
authors.initials: D
authors.lastname: Alignani
authors.affiliation: Division of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Olagüe
authors.affiliation: Division of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Africa
authors.initials: A
authors.lastname: Vales
authors.affiliation: Division of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Pedro
authors.initials: P
authors.lastname: Berraondo
authors.affiliation: Division of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain University Clinic of Navarra, University of Navarra, Pamplona, Spain CIBERehd, University of Navarra, Pamplona, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Prieto
authors.affiliation: Division of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain ggasegui@unav.es.
authors.forename: Gloria
authors.initials: G
authors.lastname: González-Aseguinolaza
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D016130:Immunophenotyping; D016898:Interferon-alpha / Q000235:genetics / Q000494:pharmacology*; D007958:Leukocyte Count; D007962:Leukocytes / Q000166:cytology / Q000378:metabolism; D038041:Lymphopoiesis / Q000187:drug effects* / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D016898:Interferon-alpha; D014157:Transcription Factors