title: The tumor suppressor p15Ink4b regulates the differentiation and maturation of conventional dendritic cells.
abstract: The tumor suppressor p15Ink4b is frequently inactivated by methylation in acute myeloid leukemia and premalignant myeloid disorders. Dendritic cells (DCs) as potent APCs play critical regulatory roles in antileukemic immune responses. In the present study, we investigated whether p15Ink4b can function as modulator of DC development. The expression of p15Ink4b is induced strongly during differentiation and activation of DCs, and its loss resulted in significant quantitative and qualitative impairments of conventional DC (cDC) development. Accordingly, ex vivo-generated BM-derived DCs from p15Ink4b-knockout mice express significantly decreased levels of the antigen-presenting (MHC II) and costimulatory (CD80 and CD86) molecules and have impaired immunostimulatory functions, such as antigen uptake and T-cell stimulation. Reexpression of p15Ink4b in progenitors restored these defects, and confirmed a positive role for p15Ink4b during cDC differentiation and maturation. Furthermore, we have shown herein that p15Ink4b expression increases phosphorylation of Erk1/Erk2 kinases, which leads to an elevated activity of the PU.1 transcription factor. In conclusion, our results establish p15Ink4b as an important modulator of cDC development and implicate a novel function for this tumor suppressor in the regulation of adaptive immune responses.
authors.affiliation: Laboratory of Cellular Oncology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Joanna
authors.initials: J
authors.lastname: Fares
authors.forename: Richard
authors.initials: R
authors.lastname: Koller
authors.forename: Rita
authors.initials: R
authors.lastname: Humeniuk
authors.forename: Linda
authors.initials: L
authors.lastname: Wolff
authors.forename: Juraj
authors.initials: J
authors.lastname: Bies
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics*; D002478:Cells, Cultured; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019175:DNA Methylation / Q000502:physiology; D003713:Dendritic Cells / Q000378:metabolism / Q000502:physiology*; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000276:immunology / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology
chemical_list: D050762:Cyclin-Dependent Kinase Inhibitor p15; D025521:Tumor Suppressor Proteins