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*
Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA 98103, and Department of Immunology and Medicine, University of Washington, Seattle, WA 98195;
Immunotherapy and Gene Therapy Program, H. S. Raffaele, Milan, Italy; and
Cancer Research Campaign Institute for Cancer Studies, University of Birmingham, Birmingham, United Kingdom
Due to their potent immunostimulatory capacity, dendritic cells
(DC) have become the centerpiece of many vaccine regimens. Immature DC
(DCimm) capture, process, and present Ags to
CD4+ lymphocytes, which reciprocally activate
DCimm through CD40, and the resulting mature DC
(DCmat) loose phagocytic capacity, but acquire the
ability to efficiently stimulate CD8+ lymphocytes.
Recombinant vaccinia viruses (rVV) provide a rapid, easy, and efficient
method to introduce Ags into DC, but we observed that rVV infection of
DCimm results in blockade of DC maturation in response
to all activation signals, including CD40L, monocyte-conditioned
medium, LPS, TNF-
, and poly(I:C), and failure to induce a
CD8+ response. By contrast, DCmat can be
infected with rVV and induce a CD8+ response, but, having
lost phagocytic activity, fail to process the Ag via the exogenous
class II pathway. To overcome these limitations, we used the CMV
protein pp65 as a model Ag and designed a gene containing the
lysosomal-associated membrane protein 1 targeting sequence
(Sig-pp65-LAMP1) to target pp65 to the class II compartment.
DCmat infected with rVV-Sig-pp65-LAMP1 induced
proliferation of pp65-specific CD4+ clones and efficiently
induced a pp65-specific CD4+ response, suggesting that
after DC maturation the intracellular processing machinery for class II
remains intact for at least 16 h. Moreover, infection of
DCmat with rVV-Sig-pp65-LAMP1 resulted in at least
equivalent presentation to CD8+ cells as infection with
rVV-pp65. These results demonstrate that despite rVV interference with
DCimm maturation, a single targeting vector can deliver
Ags to DCmat for the effective simultaneous stimulation
of both CD4+ and CD8+
cells.
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