title: Proteasomes, TAP, and endoplasmic reticulum-associated aminopeptidase associated with antigen processing control CD4+ Th cell responses by regulating indirect presentation of MHC class II-restricted cytoplasmic antigens.
abstract: Cytoplasmic Ags derived from viruses, cytosolic bacteria, tumors, and allografts are presented to T cells by MHC class I or class II molecules. In the case of class II-restricted Ags, professional APCs acquire them during uptake of dead class II-negative cells and present them via a process called indirect presentation. It is generally assumed that the cytosolic Ag-processing machinery, which supplies peptides for presentation by class I molecules, plays very little role in indirect presentation of class II-restricted cytoplasmic Ags. Remarkably, upon testing this assumption, we found that proteasomes, TAP, and endoplasmic reticulum-associated aminopeptidase associated with Ag processing, but not tapasin, partially destroyed or removed cytoplasmic class II-restricted Ags, such that their inhibition or deficiency led to dramatically increased Th cell responses to allograft (HY) and microbial (Listeria monocytogenes) Ags, both of which are indirectly presented. This effect was neither due to enhanced endoplasmic reticulum-associated degradation nor competition for Ag between class I and class II molecules. From these findings, a novel model emerged in which the cytosolic Ag-processing machinery regulates the quantity of cytoplasmic peptides available for presentation by class II molecules and, hence, modulates Th cell responses.
authors.affiliation: Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232-2363, USA.
authors.forename: Srdjan M
authors.initials: SM
authors.lastname: Dragovic
authors.forename: Timothy
authors.initials: T
authors.lastname: Hill
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Christianson
authors.forename: Sungjune
authors.initials: S
authors.lastname: Kim
authors.forename: Tim
authors.initials: T
authors.lastname: Elliott
authors.forename: Diane
authors.initials: D
authors.lastname: Scott
authors.forename: Derry C
authors.initials: DC
authors.lastname: Roopenian
authors.forename: Luc
authors.initials: L
authors.lastname: Van Kaer
authors.forename: Sebastian
authors.initials: S
authors.lastname: Joyce
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000276:immunology*; D000626:Aminopeptidases / Q000276:immunology*; D017951:Antigen Presentation / Q000276:immunology*; D000942:Antigens, Bacterial / Q000276:immunology; D003593:Cytoplasm / Q000276:immunology; D004721:Endoplasmic Reticulum; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D008089:Listeria monocytogenes / Q000276:immunology; D046988:Proteasome Endopeptidase Complex / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D014184:Transplantation, Homologous / Q000276:immunology
chemical_list: D018528:ATP-Binding Cassette Transporters; D000942:Antigens, Bacterial; D000949:Histocompatibility Antigens Class II; C477327:transporter associated with antigen processing (TAP); D000626:Aminopeptidases; D046988:Proteasome Endopeptidase Complex