title: Timing and intensity of exposure to interferon-γ critically determines the function of monocyte-derived dendritic cells.
abstract: A growing body of evidence suggests that inflammatory cytokines have a dualistic role in immunity. In this study, we sought to determine the direct effects of interferon-γ (IFN-γ) on the differentiation and maturation of human peripheral blood monocyte-derived dendritic cells (moDC). Here, we report that following differentiation of monocytes into moDC with granulocyte-macrophage colony-stimulating factor and interleukin-4, IFN-γ induces moDC maturation and up-regulates the co-stimulatory markers CD80/CD86/CD95 and MHC Class I, enabling moDC to effectively generate antigen-specific CD4(+) and CD8(+) T-cell responses for multiple viral and tumour antigens. Early exposure of monocytes to high concentrations of IFN-γ during differentiation promotes the formation of macrophages. However, under low concentrations of IFN-γ, monocytes continue to differentiate into dendritic cells possessing a unique gene-expression profile, resulting in impairments in subsequent maturation by IFN-γ or lipopolysaccharide and an inability to generate effective antigen-specific CD4(+) and CD8(+) T-cell responses. These findings demonstrate that IFN-γ imparts differential programmes on moDC that shape the antigen-specific T-cell responses they induce. Timing and intensity of exposure to IFN-γ can therefore determine the functional capacity of moDC.
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Sid P
authors.initials: SP
authors.lastname: Kerkar
authors.forename: Dhanalakshmi
authors.initials: D
authors.lastname: Chinnasamy
authors.forename: Neima
authors.initials: N
authors.lastname: Hadi
authors.forename: Jan
authors.initials: J
authors.lastname: Melenhorst
authors.forename: Pawel
authors.initials: P
authors.lastname: Muranski
authors.forename: Alexandros
authors.initials: A
authors.lastname: Spyridonidis
authors.forename: Sawa
authors.initials: S
authors.lastname: Ito
authors.forename: Gerrit
authors.initials: G
authors.lastname: Weber
authors.forename: Fang
authors.initials: F
authors.lastname: Yin
authors.forename: Nancy
authors.initials: N
authors.lastname: Hensel
authors.forename: Ena
authors.initials: E
authors.lastname: Wang
authors.forename: Francesco M
authors.initials: FM
authors.lastname: Marincola
authors.forename: Austin John
authors.initials: AJ
authors.lastname: Barrett
mesh_terms: D002454:Cell Differentiation / Q000276:immunology*; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology*; D009000:Monocytes / Q000166:cytology* / Q000276:immunology*; D059467:Transcriptome
chemical_list: D016207:Cytokines; D007371:Interferon-gamma
keywords: T lymphocytes; antigen presentation; dendritic cells; inflammation; interferon-γ