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*
Molecular Immunology Group, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, U.K.; and
Millennium Pharmaceuticals, Cambridge, MA 02139
Priming of melan-A26/27–35-specific CTL occurs
only in a fraction of late stage melanoma patients, whereas during the
early stages of the disease and in healthy volunteers, melan-A CTL have
functional and phenotypic markers consistent with a naive phenotype. To
study the requirements for expansion of naive melan-A CTL from healthy
donors, we set up an in vitro priming protocol and, using tetramer
assays, we demonstrate that the activity and phenotype of the expanded
melan-A CTL are profoundly influenced by the type of APC used. Priming
by nonprofessional APC leads to expansion of melan-A CTL with reduced
cytolytic activity and low level of IFN-
secretion. In contrast,
mature dendritic cells (DC) expand cytolytic and IFN--producing
melan-A CTL. Priming by mature DC is also efficient at low peptide
concentration and requires only one round of stimulation. Finally, we
observed that a significant fraction of CD45RO+ melan-A CTL
primed by mature DC expresses high levels of the homing receptor CD62L,
whereas CTL primed by nonprofessional APC express CD62L in lower
percentages and at lower levels. These results suggest that suboptimal
priming by nonprofessional APC could account for the presence in vivo
of dysfunctional cells and strongly support the immunotherapeutic use
of mature DC for expansion of effector and memory Ag-specific
CTL.
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