title: Usp18 promotes conventional CD11b+ dendritic cell development.
abstract: Dendritic cells (DCs) represent the key cells linking innate and adaptive immune responses. It is critical to understand the molecular factors regulating DC differentiation. Usp18 is an IFN-inducible member of the ubiquitin-specific protease family, which deconjugates ubiquitin-like modifier ISG15 from target proteins and competitively inhibits IFN-α/β-induced JAK/STAT activation. This study demonstrates that the frequency of conventional CD11b(+) DCs in the spleen of Usp18(-/-) mice was significantly reduced, whereas the frequencies of conventional CD8(+) DCs and plasmacytoid DCs remained normal. In addition, Usp18(-/-) bone marrow (BM) cells generate DCs less efficiently in GM-CSF-supplemented culture, demonstrating a fundamental defect throughout the DC differentiation pathway. Usp18(-/-) BM cells were rescued by exogenous expression of either wild-type or deconjugation-inactive Usp18, and superimposition of an IFN-α/β receptor knockout returned in vivo DC populations to normal, clearly showing that the defect seen is due solely to Usp18's effect on IFN signaling. Finally, Usp18(-/-) BM-derived DCs expressed high levels of SOCS1/SOCS3, known inhibitors of GM-CSF signaling, providing a mechanistic explanation for the phenotype. In conclusion, we have identified a novel role of Usp18 in modulating conventional CD11b(+) DC development via its inhibitory effect on type I IFN signaling.
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Xiu-Li
authors.initials: XL
authors.lastname: Cong
authors.forename: Miao-Chia
authors.initials: MC
authors.lastname: Lo
authors.forename: Brian A
authors.initials: BA
authors.lastname: Reuter
authors.forename: Ming
authors.initials: M
authors.lastname: Yan
authors.forename: Jun-Bao
authors.initials: JB
authors.lastname: Fan
authors.forename: Dong-Er
authors.initials: DE
authors.lastname: Zhang
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000096:biosynthesis*; D016827:CD8 Antigens / Q000096:biosynthesis; D002452:Cell Count; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000201:enzymology / Q000276:immunology*; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D010450:Endopeptidases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000502:physiology; D006133:Growth Substances / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis / Q000502:physiology; D043222:Ubiquitin Thiolesterase
chemical_list: D039481:CD11b Antigen; D016827:CD8 Antigens; D006133:Growth Substances; C491590:Socs1 protein, mouse; C491411:Socs3 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D010450:Endopeptidases; C118306:Usp18 protein, mouse; D043222:Ubiquitin Thiolesterase