Lipopeptide presentation pathway in dendritic cells

Lipopeptides are currently being evaluated as candidate vaccines in human v olunteers. They elicit cytotoxic responses from CD8(+) T lymphocytes, where as peptides without a lipidic moiety usually do not. The exact processing a nd 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 lipope ptides derived from an HLA-A2.1-restricted HIV-1 Reverse Transcriptase epit ope, 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 f unctional stimulation of CD8(+) T lymphocytes specific for the epitopes, qu antified by Interferon-gamma ELISPOT assays. The peptide alone was not visu alized inside the DC and was only presented through direct surface associat ion 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 app roach, cross-presentation pathways can be better defined and vaccine lipope ptides can be further optimized for MHC class I association in human dendri tic cells. (C) 2001 Elsevier Science B.V. All rights reserved.