title: Ubiquitination of CD86 is a key mechanism in regulating antigen presentation by dendritic cells.
abstract: Dendritic cells (DCs) require costimulatory molecules such as CD86 to efficiently activate T cells for the induction of adaptive immunity. DCs maintain minimal levels of CD86 expression at rest, but upregulate levels upon LPS stimulation. LPS-stimulated DCs produce the immune suppressive cytokine IL-10 that acts in an autocrine manner to regulate CD86 levels. Interestingly, the underlying molecular mechanism behind the tight control of CD86 is not completely understood. In this study, we report that CD86 is ubiquitinated in DCs via MARCH1 E3 ubiquitin ligase and that this ubiquitination plays a key role in CD86 regulation. Ubiquitination at lysine 267 played the most critical role for this regulation. CD86 is ubiquitinated in MARCH1-deficient DCs to a much lesser degree than in wild-type DCs, which also correlated with a significant increase in CD86 expression. Importantly, CD86 is continuously ubiquitinated in DCs following activation by LPS, and this was due to the autocrine IL-10 inhibition of MARCH1 downregulation. Accordingly, DCs lacking MARCH1 and DCs expressing ubiquitination-resistant mutant CD86 both failed to regulate CD86 in response to autocrine IL-10. DCs expressing ubiquitination-resistant mutant CD86 failed to control their T cell-activating abilities at rest as well as in response to autocrine IL-10. These studies suggest that ubiquitination serves as an important mechanism by which DCs control CD86 expression and regulate their Ag-presenting functions.
authors.affiliation: Department of Microbiology and Immunology, Sandler Asthma Basic Research Center, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Günther
authors.initials: G
authors.lastname: Baravalle
authors.forename: Hyesuk
authors.initials: H
authors.lastname: Park
authors.forename: Megan
authors.initials: M
authors.lastname: McSweeney
authors.forename: Mari
authors.initials: M
authors.lastname: Ohmura-Hoshino
authors.forename: Yohei
authors.initials: Y
authors.lastname: Matsuki
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ishido
authors.forename: Jeoung-Sook
authors.initials: JS
authors.lastname: Shin
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D051940:B7-2 Antigen / Q000276:immunology / Q000378:metabolism*; D015153:Blotting, Western; D002469:Cell Separation; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000276:immunology*; D047468:Immunoprecipitation; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology; D044767:Ubiquitin-Protein Ligases / Q000276:immunology / Q000378:metabolism; D054875:Ubiquitination / Q000276:immunology*
chemical_list: D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; C545340:MARCH1 protein, mouse; D044767:Ubiquitin-Protein Ligases