title: Activation of human CD4+ T cells by targeting MHC class II epitopes to endosomal compartments using human CD1 tail sequences.
abstract: Distinct CD4(+) T-cell epitopes within the same protein can be optimally processed and loaded into major histocompatibility complex (MHC) class II molecules in disparate endosomal compartments. The CD1 protein isoforms traffic to these same endosomal compartments as directed by unique cytoplasmic tail sequences, therefore we reasoned that antigen/CD1 chimeras containing the different CD1 cytoplasmic tail sequences could optimally target antigens to the MHC class II antigen presentation pathway. Evaluation of trafficking patterns revealed that all four human CD1-derived targeting sequences delivered antigen to the MHC class II antigen presentation pathway, to early/recycling, early/sorting and late endosomes/lysosomes. There was a preferential requirement for different CD1 targeting sequences for the optimal presentation of an MHC class II epitope in the following hierarchy: CD1b > CD1d = CD1c > > > CD1a or untargeted antigen. Therefore, the substitution of the CD1 ectodomain with heterologous proteins results in their traffic to distinct intracellular locations that intersect with MHC class II and this differential distribution leads to specific functional outcomes with respect to MHC class II antigen presentation. These findings may have implications in designing DNA vaccines, providing a greater variety of tools to generate T-cell responses against microbial pathogens or tumours.
authors.affiliation: Discovery Translation Unit, Buck Institute, Novato, CA, USA.
authors.forename: Kayvan R
authors.initials: KR
authors.lastname: Niazi
authors.forename: Maria-Teresa
authors.initials: MT
authors.lastname: Ochoa
authors.forename: Peter A
authors.initials: PA
authors.lastname: Sieling
authors.forename: Nanette E
authors.initials: NE
authors.lastname: Rooke
authors.forename: Anna K
authors.initials: AK
authors.lastname: Peter
authors.forename: Pamela
authors.initials: P
authors.lastname: Mollahan
authors.forename: Micah
authors.initials: M
authors.lastname: Dickey
authors.forename: Shahrooz
authors.initials: S
authors.lastname: Rabizadeh
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Rea
authors.forename: Robert L
authors.initials: RL
authors.lastname: Modlin
mesh_terms: D017951:Antigen Presentation / Q000276:immunology; D000942:Antigens, Bacterial / Q000276:immunology; D018949:Antigens, CD1 / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018835:Chaperonin 10 / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D011992:Endosomes / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D049452:Green Fluorescent Proteins; D006367:HeLa Cells; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D009166:Mycobacterium leprae / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000276:immunology; D011994:Recombinant Proteins; D014162:Transfection
chemical_list: D000942:Antigens, Bacterial; D018949:Antigens, CD1; D018835:Chaperonin 10; D018984:Epitopes, T-Lymphocyte; D000949:Histocompatibility Antigens Class II; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D049452:Green Fluorescent Proteins; D007371:Interferon-gamma