Chronic exposure to IFNα drives medullar lymphopoiesis towards T-cell differentiation in mice
Marianna Di Scala,
Irene Gil-Fariña,
Lucia Vanrell,
Rodrigo Sánchez-Bayona,
Diego Alignani,
Cristina Olagüe,
Africa Vales,
Pedro Berraondo,
Jesús Prieto,
Gloria González-Aseguinolaza
Affiliations
Marianna Di Scala
Division of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
Irene Gil-Fariña
Division of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
Lucia Vanrell
Division of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
Rodrigo Sánchez-Bayona
Division of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
Diego Alignani
Department of Instrumental Techniques-Cytometry Unit, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
Cristina Olagüe
Division of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
Africa Vales
Division of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
Pedro Berraondo
Division of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
Jesús Prieto
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
Gloria González-Aseguinolaza
Division of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
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.
