Variable processing and cross-presentation of HIV by dendritic cells and macrophages shapes CTL immunodominance and immune escape

PLoS Pathogens
Jens DinterSylvie Le Gall

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 com...Continue Reading

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Citations

Oct 21, 2015·Frontiers in Immunology·Mark A BrockmanZabrina L Brumme
Jun 1, 2016·Frontiers in Immunology·Aram Nikolai AndersenInger Øynebråten
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Methods Mentioned

BETA
ELISA
flow cytometry

Software Mentioned

GraphPad Prism
Proteome Discoverer

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