Lipopeptide presentation pathway in dendritic cells.
Lipopeptides are currently being evaluated as candidate vaccines in human volunteers. They elicit cytotoxic responses from CD8(+) T lymphocytes, whereas peptides without a lipidic moiety usually do not. The exact processing and presentation pathways leading to association with MHC class I molecules has not yet been defined. This is of particular interest in dendritic cells, which are required for primary T cell stimulation. We have tracked lipopeptides derived from an HLA-A2.1-restricted HIV-1 Reverse Transcriptase epitope, by N-terminal addition of an N-epsilon-palmitoyl-lysine. Entry of the lipopeptides into human monocyte-derived dendritic cells (MDC) was mediated by endocytosis, as assessed by colocalization using analogs labelled with rhodamine, and by confocal microscopy. This internalization in DC induced functional stimulation of CD8(+) T lymphocytes specific for the epitopes, quantified by Interferon-gamma ELISPOT assays. The peptide alone was not visualized inside the DC and was only presented through direct surface association to HLA-A*0201. Therefore, lipopeptides provide a model system to define precisely the cross-presentation pathways that lead exogenous proteins to associate with class I MHC molecules within dendritic cells. Using this approach, cross-presentation pathways can be better defined and vaccine lipopeptides can be further optimized for MHC class I association in human dendritic cells.
Hosmalin
A
A
INSERM U445, ICGM, 27 rue du Faubourg St-Jacques 75014, Paris, France. hosmalin@cochin.inserm.fr
Andrieu
M
M
Loing
E
E
Desoutter
J F
JF
Hanau
D
D
Gras-Masse
H
H
Dautry-Varsat
A
A
Guillet
J G
JG
D016915:AIDS Vaccines / Q000494:pharmacology; D017951:Antigen Presentation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D000939:Epitopes; D054303:HIV Reverse Transcriptase / Q000276:immunology; D015789:HLA-A2 Antigen; D006801:Humans; D066298:In Vitro Techniques; D008074:Lipoproteins / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology
D016915:AIDS Vaccines; D000939:Epitopes; D015789:HLA-A2 Antigen; D008074:Lipoproteins; D010446:Peptide Fragments; D054303:HIV Reverse Transcriptase