title: B7-1/2, but not PD-L1/2 molecules, are required on IL-10-treated tolerogenic DC and DC-derived exosomes for in vivo function.
abstract: Costimulatory molecules, such as B7-1/2 and PD-L1/2 play an important role in the function of APC. The regulation of the surface levels of costimulatory molecules is one mechanism by which APC maintain the balance between tolerance and immunity. We examined the contributions of B7-1/2 and PD-L1/2 to the function of IL-10-treated, immunosuppressive DC as well as therapeutic exosomes derived from these DC. IL-10 treatment of DC significantly downregulated surface expression of MHC II, B7-1, B7-2, and decreased levels of MHC I and PD-L2. IL-10 treatment of DC resulted in a modified costimulatory profile of DC-secreted exosomes with a reduction in B7-1, PD-L1 and PD-L2. We further demonstrate that absence of B7-1 or B7-2 on donor DC results in a loss of ability of IL-10-treated DC and their exosomes to suppress the delayed-type hypersensitivity response, whereas IL-10-treated DC deficient in PD-L1/2 as well as their secreted exosomes retained the ability to suppress delayed-type hypersensitivity responses. We conclude that B7-1 and B7-2, but not PD-L1 and PD-L2, on IL-10-treated DC and DC-derived exosomes play a critical role in immunosuppressive functions of both DC and exosomes.
authors.affiliation: Department of Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Ruffner
authors.forename: Seon Hee
authors.initials: SH
authors.lastname: Kim
authors.forename: Nicole R
authors.initials: NR
authors.lastname: Bianco
authors.forename: Loise M
authors.initials: LM
authors.lastname: Francisco
authors.forename: Arlene H
authors.initials: AH
authors.lastname: Sharpe
authors.forename: Paul D
authors.initials: PD
authors.lastname: Robbins
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000276:immunology; D018122:B7-1 Antigen / Q000276:immunology*; D051940:B7-2 Antigen / Q000276:immunology*; D060890:B7-H1 Antigen; D015153:Blotting, Western; D002469:Cell Separation; D003713:Dendritic Cells / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D055354:Exosomes / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006968:Hypersensitivity, Delayed; D007108:Immune Tolerance / Q000276:immunology*; D016753:Interleukin-10 / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010455:Peptides / Q000276:immunology; D061027:Programmed Cell Death 1 Ligand 2 Protein
chemical_list: D018122:B7-1 Antigen; D051940:B7-2 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D008562:Membrane Glycoproteins; C556978:Pdcd1lg2 protein, mouse; D010455:Peptides; D061027:Programmed Cell Death 1 Ligand 2 Protein; D016753:Interleukin-10