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*
Melbourne Tumor Biology Branch, Ludwig Institute for Cancer Research, Austin and Repatriation Medical Centre, Heidelberg, Victoria, Australia;
University of Heidelberg, Heidelberg, Germany; and
Department of Molecular Biology and Immunology, CSL Ltd., Parkville, Melbourne, Australia
This study investigates the differential capacity of TAP-deficient
T2 cells, TAP-competent EBV cells, and immature and mature dendritic
cells to present peptides to preformed CTL lines. It demonstrates that
presentation of exogenous peptides involves peptide uptake and loading
onto newly synthesized MHC class I molecules. This mechanism was best
demonstrated for low affinity peptides in the presence of irrelevant
peptides competing for HLA binding sites. Under these circumstances,
inhibition of protein synthesis with cycloheximide or vesicular
trafficking with brefeldin A significantly reduced the presentation of
low affinity peptides. This was not restored by adding exogenous
2-microglobulin to stabilize the MHC complex on the cell
surface. In contrast, presentation of high affinity peptides was not
sensitive to cycloheximide or brefeldin A, which suggests that
different mechanisms may operate for presentation of high and low
affinity peptides by TAP-competent cells. High affinity peptides can
apparently compete with peptides in preloaded MHC class I molecules at
the cell surface, whereas low affinity peptides require empty MHC
molecules within cells. Accordingly, very high concentrations of
exogenous low affinity peptides in conjunction with active MHC class I
metabolism were required to allow successful presentation against a
background of competing intracellular high affinity peptides in
TAP-competent cells. These findings have implications for the design of
peptide and protein-based vaccines.
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