title: Type I IFN drives a distinctive dendritic cell maturation phenotype that allows continued class II MHC synthesis and antigen processing.
abstract: Microbial molecules or cytokines can stimulate dendritic cell (DC) maturation, which involves DC migration to lymph nodes and enhanced presentation of Ag to launch T cell responses. Microbial TLR agonists are the most studied inducers of DC maturation, but type I IFN (IFN-I) also promotes DC maturation. In response to TLR stimulation, DC maturation involves a burst of Ag processing with enhanced expression of peptide-class II MHC complexes and costimulator molecules. Subsequently, class II MHC (MHC-II) synthesis and expression in intracellular vacuolar compartments is inhibited, decreasing Ag processing function. This limits presentation to a cohort of Ags kinetically associated with the maturation stimulus and excludes presentation of Ags subsequently experienced by the DC. In contrast, our studies show that IFN-I enhances DC expression of MHC-II and costimulatory molecules without a concomitant inhibition of subsequent MHC-II synthesis and Ag processing. Expression of mRNA for MHC-II and the transcription factor CIITA is inhibited in DCs treated with TLR agonists but maintained in cells treated with IFN-I. After stimulation with IFN-I, MHC-II expression is increased on the plasma membrane but is also maintained in intracellular vacuolar compartments, consistent with sustained Ag processing function. These findings suggest that IFN-I drives a distinctive DC maturation program that enhances Ag presentation to T cells without a shutdown of Ag processing, allowing continued sampling of Ags for presentation.
authors.affiliation: Department of Pathology, Case Western Reserve University/University Hospitals Case Medical Center, Cleveland, OH 44106, USA.
authors.forename: Daimon P
authors.initials: DP
authors.lastname: Simmons
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Wearsch
authors.forename: David H
authors.initials: DH
authors.lastname: Canaday
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Meyerson
authors.forename: Yi C
authors.initials: YC
authors.lastname: Liu
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: W Henry
authors.initials: WH
authors.lastname: Boom
authors.forename: Clifford V
authors.initials: CV
authors.lastname: Harding
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000166:cytology* / Q000187:drug effects; D004705:Endocytosis; D005786:Gene Expression Regulation / Q000276:immunology; D005802:Genes, MHC Class II; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis*; D007370:Interferon Type I / Q000494:pharmacology / Q000502:physiology*; D008565:Membrane Proteins / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D010641:Phenotype; D011994:Recombinant Proteins / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors; D013047:Specific Pathogen-Free Organisms; D051193:Toll-Like Receptors / Q000819:agonists; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000276:Adjuvants, Immunologic; D000949:Histocompatibility Antigens Class II; D007370:Interferon Type I; C083728:MHC class II transactivator protein; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011994:Recombinant Proteins; D018894:Reverse Transcriptase Inhibitors; D051193:Toll-Like Receptors; D015534:Trans-Activators; C084881:flt3 ligand protein; D016178:Granulocyte-Macrophage Colony-Stimulating Factor