title: CD83 increases MHC II and CD86 on dendritic cells by opposing IL-10-driven MARCH1-mediated ubiquitination and degradation.
abstract: Effective vaccine adjuvants must induce expression of major histocompatibility (MHC) class II proteins and the costimulatory molecule CD86 on dendritic cells (DCs). However, some adjuvants elicit production of cytokines resulting in adverse inflammatory consequences. Development of agents that selectively increase MHC class II and CD86 expression without triggering unwanted cytokine production requires a better understanding of the molecular mechanisms influencing the production and degradation of MHC class II and CD86 in DCs. Here, we investigate how CD83, an immunoglobulin protein expressed on the surface of mature DCs, promotes MHC class II and CD86 expression. Using mice with an N-ethyl-N-nitrosourea-induced mutation eliminating the transmembrane (TM) region of CD83, we found that the TM domain of CD83 enhances MHC class II and CD86 expression by blocking MHC class II association with the ubiquitin ligase MARCH1. The TM region of CD83 blocks interleukin 10-driven, MARCH1-dependent ubiquitination and degradation of MHC class II and CD86 in DCs. Exploiting this posttranslational pathway for boosting MHC class II and CD86 expression on DCs may provide an opportunity to enhance the immunogenicity of vaccines.
authors.affiliation: Immunology Department, John Curtin School of Medical Research, the Australian National University, Canberra ACT 2601, Australia.
authors.forename: Lina E
authors.initials: LE
authors.lastname: Tze
authors.forename: Keisuke
authors.initials: K
authors.lastname: Horikawa
authors.forename: Heather
authors.initials: H
authors.lastname: Domaschenz
authors.forename: Debbie R
authors.initials: DR
authors.lastname: Howard
authors.forename: Carla M
authors.initials: CM
authors.lastname: Roots
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Rigby
authors.forename: David A
authors.initials: DA
authors.lastname: Way
authors.forename: Mari
authors.initials: M
authors.lastname: Ohmura-Hoshino
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ishido
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Andoniou
authors.forename: Mariapia A
authors.initials: MA
authors.lastname: Degli-Esposti
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Goodnow
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D051940:B7-2 Antigen / Q000276:immunology*; D001483:Base Sequence; D002462:Cell Membrane / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D057809:HEK293 Cells; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006801:Humans; D007136:Immunoglobulins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D016753:Interleukin-10 / Q000276:immunology*; D008297:Male; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008969:Molecular Sequence Data; D016415:Sequence Alignment; D044767:Ubiquitin-Protein Ligases / Q000276:immunology / Q000378:metabolism*; D054875:Ubiquitination; D000097802:CD83 Antigen
chemical_list: D015703:Antigens, CD; D051940:B7-2 Antigen; D000949:Histocompatibility Antigens Class II; D007136:Immunoglobulins; D016753:Interleukin-10; D008562:Membrane Glycoproteins; D044767:Ubiquitin-Protein Ligases; D000097802:CD83 Antigen; C497965:Cd86 protein, mouse; C545340:MARCH1 protein, mouse