title: Variable processing and cross-presentation of HIV by dendritic cells and macrophages shapes CTL immunodominance and immune escape.
abstract: Dendritic cells (DCs) and macrophages (Møs) internalize and process exogenous HIV-derived antigens for cross-presentation by MHC-I to cytotoxic CD8⁺ T cells (CTL). However, how degradation patterns of HIV antigens in the cross-presentation pathways affect immunodominance and immune escape is poorly defined. Here, we studied the processing and cross-presentation of dominant and subdominant HIV-1 Gag-derived epitopes and HLA-restricted mutants by monocyte-derived DCs and Møs. The cross-presentation of HIV proteins by both DCs and Møs led to higher CTL responses specific for immunodominant epitopes. The low CTL responses to subdominant epitopes were increased by pretreatment of target cells with peptidase inhibitors, suggestive of higher intracellular degradation of the corresponding peptides. Using DC and Mø cell extracts as a source of cytosolic, endosomal or lysosomal proteases to degrade long HIV peptides, we identified by mass spectrometry cell-specific and compartment-specific degradation patterns, which favored the production of peptides containing immunodominant epitopes in all compartments. The intracellular stability of optimal HIV-1 epitopes prior to loading onto MHC was highly variable and sequence-dependent in all compartments, and followed CTL hierarchy with immunodominant epitopes presenting higher stability rates. Common HLA-associated mutations in a dominant epitope appearing during acute HIV infection modified the degradation patterns of long HIV peptides, reduced intracellular stability and epitope production in cross-presentation-competent cell compartments, showing that impaired epitope production in the cross-presentation pathway contributes to immune escape. These findings highlight the contribution of degradation patterns in the cross-presentation pathway to HIV immunodominance and provide the first demonstration of immune escape affecting epitope cross-presentation.
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, Harvard Medical School, Cambridge, Massachusetts, United States of America.
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, Massachusetts, United States of America.
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, Massachusetts, United States of America.
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, Massachusetts, United States of America.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Berberich
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, Harvard Medical School, Cambridge, Massachusetts, United States of America.
authors.forename: Georgio
authors.initials: G
authors.lastname: Kourjian
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, Harvard Medical School, Cambridge, Massachusetts, United States of America.
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, Massachusetts, United States of America.
authors.forename: Duong
authors.initials: D
authors.lastname: Chu
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, Harvard Medical School, Cambridge, Massachusetts, United States of America.
authors.forename: Hang
authors.initials: H
authors.lastname: Su
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, Harvard Medical School, Cambridge, Massachusetts, United States of America.
authors.forename: Shao Chong
authors.initials: SC
authors.lastname: Zhang
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Massachusetts General Hospital, Harvard Medical School, Cambridge, Massachusetts, United States of America.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Le Gall
mesh_terms: D045142:Cross-Priming / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D015658:HIV Infections / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D057131:Immune Evasion / Q000276:immunology*; D016056:Immunodominant Epitopes / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D013058:Mass Spectrometry; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes