title: HLA-DR peptide occupancy can be regulated with a wide variety of small molecules.
abstract: HLA-DR is the most commonly expressed and likely the most medically important human MHC class II, antigen presenting protein. In a normal immune response, HLA-DR binds to antigenic peptide and the HLA-DR/peptide complex binds to a T-cell receptor, thus contributing to T-cell activation and stimulation of an immune response against the antigen. When foreign antigen is not present, HLA-DR binds endogenous peptide which, under normal conditions does not stimulate an immune response. In most cases, the human peptide is CLIP, but a certain percentage of HLA-DR molecules will be present at the cell surface with other human peptides. We have recently shown that cell surface, CLIP/HLA-DR ratios are a measure of peptide heterogeneity, and in particular, changes in CLIP/HLA-DR ratios represent changes in the occupancy of HLA-DR by other, endogenous peptides. For example, treatment of cells with the HDAC inhibitor, Entinostat, leads to an upregulation of Cathepsin L1 and replacement of Cathepsin L1 senstitive peptides with HLA-DR binding, Cathepsin L1 resistant peptides, an alteration that can be at least partially assessed via assessment of CLIP/HLA-DR cell surface ratios. Here we assay for CLIP/HLA-DR ratios following treatment of immortalized B-cells with a variety of common drugs, almost all of which indicate significant changes in the CLIP/HLA-DR ratios. Furthermore, the CLIP/HLA-DR ratio changes parallel the impact of the drug panoply on cell viability, suggesting that alterations in the HLA-DR peptidome are governed by a variety of mechanisms, rather than exclusively dependent on a dedicated peptide loading process. These results raise questions about how FDA approved drugs may affect the immune response, and whether any of these drugs could be useful as vaccine adjuvants?
authors.affiliation: a Department of Molecular Medicine , Morsani College of Medicine, University of South Florida , Tampa , FL , USA.
authors.forename: Francesca
authors.initials: F
authors.lastname: Blazekovic
authors.affiliation: a Department of Molecular Medicine , Morsani College of Medicine, University of South Florida , Tampa , FL , USA.
authors.forename: Dana
authors.initials: D
authors.lastname: Odukoya
authors.affiliation: a Department of Molecular Medicine , Morsani College of Medicine, University of South Florida , Tampa , FL , USA.
authors.forename: Shanitra N
authors.initials: SN
authors.lastname: Butler
authors.affiliation: a Department of Molecular Medicine , Morsani College of Medicine, University of South Florida , Tampa , FL , USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Mauro
authors.affiliation: a Department of Molecular Medicine , Morsani College of Medicine, University of South Florida , Tampa , FL , USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Ramsamooj
authors.affiliation: a Department of Molecular Medicine , Morsani College of Medicine, University of South Florida , Tampa , FL , USA.
authors.forename: Erika
authors.initials: E
authors.lastname: Puleo
authors.affiliation: a Department of Molecular Medicine , Morsani College of Medicine, University of South Florida , Tampa , FL , USA.
authors.forename: Karoly
authors.initials: K
authors.lastname: Szekeres
authors.affiliation: b Department of Chemistry and Biochemistry , Queens College and the Graduate Center of the City University of New York , Queens , NY , USA.
authors.forename: Dibyendu
authors.initials: D
authors.lastname: Dana
authors.affiliation: b Department of Chemistry and Biochemistry , Queens College and the Graduate Center of the City University of New York , Queens , NY , USA.
authors.forename: Sanjai
authors.initials: S
authors.lastname: Kumar
authors.affiliation: c Department of Medicine ; Melanoma and Immunotherapeutic Service, Memorial Sloan Kettering Cancer Center , New York , NY , USA.
authors.forename: Govind
authors.initials: G
authors.lastname: Ragupathi
authors.affiliation: a Department of Molecular Medicine , Morsani College of Medicine, University of South Florida , Tampa , FL , USA.|d Immunology Program, H. Lee Moffitt Cancer Center and Research Institute , Tampa , FL , USA.
authors.forename: George
authors.initials: G
authors.lastname: Blanck
mesh_terms: D017951:Antigen Presentation / Q000187:drug effects*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000032:analysis*; D001402:B-Lymphocytes / Q000737:chemistry* / Q000187:drug effects*; D006684:HLA-DR Antigens / Q000032:analysis*; D000949:Histocompatibility Antigens Class II / Q000032:analysis*; D006801:Humans
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D006684:HLA-DR Antigens; D000949:Histocompatibility Antigens Class II; C045084:invariant chain
keywords: CLIP; HLA-DR peptidome; Raji B-cells; epitope diversity; protease bioinformatics; proteases