title: Different antigen-processing activities in dendritic cells, macrophages, and monocytes lead to uneven production of HIV epitopes and affect CTL recognition.
abstract: Dendritic cells (DCs), macrophages (MPs), and monocytes are permissive to HIV. Whether they similarly process and present HIV epitopes to HIV-specific CD8 T cells is unknown despite the critical role of peptide processing and presentation for recognition and clearance of infected cells. Cytosolic peptidases degrade endogenous proteins originating from self or pathogens, exogenous Ags preprocessed in endolysosomes, thus shaping the peptidome available for endoplasmic reticulum translocation, trimming, and MHC-I presentation. In this study, we compared the capacity of DCs, MPs, and monocyte cytosolic extracts to produce epitope precursors and epitopes. We showed differences in the proteolytic activities and expression levels of cytosolic proteases between monocyte-derived DCs and MPs and upon maturation with LPS, R848, and CL097, with mature MPs having the highest activities. Using cytosol as a source of proteases to degrade epitope-containing HIV peptides, we showed by mass spectrometry that the degradation patterns of long peptides and the kinetics and amount of antigenic peptides produced differed among DCs, MPs, and monocytes. Additionally, variable intracellular stability of HIV peptides prior to loading onto MHC may accentuate the differences in epitope availability for presentation by MHC-I between these subsets. Differences in peptide degradation led to 2- to 25-fold differences in the CTL responses elicited by the degradation peptides generated in DCs, MPs, and monocytes. Differences in Ag-processing activities between these subsets might lead to variations in the timing and efficiency of recognition of HIV-infected cells by CTLs and contribute to the unequal capacity of HIV-specific CTLs to control viral load.
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, Harvard Medical School, Cambridge, MA, USA.
authors.forename: Jens
authors.initials: J
authors.lastname: Dinter
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, Harvard Medical School, Cambridge, MA, USA.
authors.forename: Pauline
authors.initials: P
authors.lastname: Gourdain
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, Harvard Medical School, Cambridge, MA, USA.
authors.forename: Nicole Y
authors.initials: NY
authors.lastname: Lai
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, Harvard Medical School, Cambridge, MA, USA.
authors.forename: Ellen
authors.initials: E
authors.lastname: Duong
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, Harvard Medical School, Cambridge, MA, USA.
authors.forename: Edith
authors.initials: E
authors.lastname: Bracho-Sanchez
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, Harvard Medical School, Cambridge, MA, USA.
authors.forename: Marijana
authors.initials: M
authors.lastname: Rucevic
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, Harvard Medical School, Cambridge, MA, USA.
authors.forename: Paul H
authors.initials: PH
authors.lastname: Liebesny
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, Harvard Medical School, Cambridge, MA, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, Harvard Medical School, Cambridge, MA, USA.
authors.forename: Mariko
authors.initials: M
authors.lastname: Shimada
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, Harvard Medical School, Cambridge, MA, USA.
authors.forename: Musie
authors.initials: M
authors.lastname: Ghebremichael
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, Harvard Medical School, Cambridge, MA, USA.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Kavanagh
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, Harvard Medical School, Cambridge, MA, USA.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Le Gall
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D000954:Antigens, Surface / Q000378:metabolism; D002461:Cell Line, Transformed; D003600:Cytosol / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D000939:Epitopes / Q000276:immunology*; D006678:HIV / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology*; D006801:Humans; D016130:Immunophenotyping; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055550:Protein Stability; D059748:Proteolysis; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D000954:Antigens, Surface; D000939:Epitopes; D010455:Peptides; D051193:Toll-Like Receptors; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex