title: Dendritic cells utilize the evolutionarily conserved WASH and retromer complexes to promote MHCII recycling and helper T cell priming.
abstract: Immature dendritic cells (DCs) maintain a highly dynamic pool of recycling MHCII that promotes sampling of environmental antigens for presentation to T helper cells. However, the molecular basis of MHCII recycling and the cellular machinery that orchestrates MHCII trafficking are incompletely understood. Using a mouse model we show that WASH, an actin regulatory protein that facilitates retromer function, is essential for MHCII recycling and efficient priming of T helper cells. We further demonstrate that WASH deficiency results in impaired MHCII surface levels, recycling, and an accumulation of polyubiquitinated MHCII complexes, which are subsequently slated for premature lysosomal degradation. Consequently, conditional deletion of the Wash gene in DCs impairs priming of both conventional and autoimmune T helper cells in vivo and attenuates disease progression in a model of experimental autoimmune encephalitis (EAE). Thus, we identify a novel mechanism in which DCs employ the evolutionarily conserved WASH and retromer complex for MHCII recycling in order to regulate T helper cell priming.
authors.affiliation: Department of Pathology and Immunology, Division of Immunobiology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Graham
authors.affiliation: Department of Immunology, Division of Oncology Research and Schulze Center for Novel Therapeutics, Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America.
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Osborne
authors.affiliation: Department of Immunology, Division of Oncology Research and Schulze Center for Novel Therapeutics, Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America.
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Piotrowski
authors.affiliation: Department of Immunology, Division of Oncology Research and Schulze Center for Novel Therapeutics, Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Gomez
authors.affiliation: Department of Pathology and Immunology, Division of Immunobiology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Grzegorz B
authors.initials: GB
authors.lastname: Gmyrek
authors.affiliation: Department of Pathology and Immunology, Division of Immunobiology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Holly M
authors.initials: HM
authors.lastname: Akilesh
authors.affiliation: Department of Pathology and Immunology, Division of Immunobiology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Adish
authors.initials: A
authors.lastname: Dani
authors.affiliation: Department of Immunology, Division of Oncology Research and Schulze Center for Novel Therapeutics, Mayo Clinic College of Medicine, Rochester, Minnesota, United States of America.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Billadeau
authors.affiliation: Department of Pathology and Immunology, Division of Immunobiology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Swat
mesh_terms: D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D003713:Dendritic Cells / Q000502:physiology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D000949:Histocompatibility Antigens Class II / Q000276:immunology* / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D054875:Ubiquitination
chemical_list: D017931:DNA Primers; D000949:Histocompatibility Antigens Class II