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Journal of Virology, October 2000, p. 9617-9628, Vol. 74, No. 20
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Recombinant Adenovirus Induces Maturation of
Dendritic Cells via an NF-
B-Dependent Pathway
Adrian E.
Morelli,1,2,*
Adriana T.
Larregina,3
Raymond W.
Ganster,2
Alan F.
Zahorchak,1,2
Jeffrey M.
Plowey,3
Takuya
Takayama,1,2
Alison J.
Logar,1,2
Paul D.
Robbins,4
Louis D.
Falo,3 and
Angus W.
Thomson1,2,4
Thomas E. Starzl Transplantation
Institute,1 Department of
Surgery,2 Department of Molecular
Genetics and Biochemistry,4 and
Department of Dermatology and the University of Pittsburgh
Cancer Institute,3 University of Pittsburgh
Medical Center, Pittsburgh, Pennsylvania 15213-2582
Received 5 May 2000/Accepted 12 July 2000
Recombinant adenovirus (rAd) infection is one of the most effective
and frequently employed methods to transduce dendritic cells (DC).
Contradictory results have been reported recently concerning the
influence of rAd on the differentiation and activation of DC. In this
report, we show that, as a result of rAd infection, mouse bone
marrow-derived immature DC upregulate expression of major
histocompatibility complex class I and II antigens, costimulatory molecules (CD40, CD80, and CD86), and the adhesion molecule CD54 (ICAM-1). rAd-transduced DC exhibited increased allostimulatory capacity and levels of interleukin-6 (IL-6), IL-12p40, IL-15, gamma
interferon, and tumor necrosis factor alpha mRNAs, without effects on
other immunoregulatory cytokine transcripts such as IL-10 or IL-12p35.
These effects were not related to specific transgenic sequences or to
rAd genome transcription. The rAd effect correlated with a rapid
increase (1 h) in the NF-
B-DNA binding activity detected by
electrophoretic mobility shift assays. rAd-induced DC maturation was
blocked by the proteasome inhibitor
N
-p-tosyl-L-lysine chloromethyl
ketone (TLCK) or by infection with rAd-I
B, an rAd-encoding the
dominant-negative form of I
B. In vivo studies showed that after
intravenous administration, rAds were rapidly entrapped in the spleen
by marginal zone DC that mobilized to T-cell areas, a phenomenon
suggesting that rAd also induced DC differentiation in vivo.
These findings may explain the immunogenicity of rAd and the
difficulties in inducing long-term antigen-specific T-cell hyporesponsiveness with rAd-transduced DC.
*
Corresponding author. Mailing address: Department of
Surgery, University of Pittsburgh Medical Center, E1504 Biomedical
Science Tower, 200 Lothrop St., Pittsburgh, PA 15213. Phone: (412)
624-6627. Fax: (412) 624-1172. E-mail:
morelli{at}imap.pitt.edu.
Journal of Virology, October 2000, p. 9617-9628, Vol. 74, No. 20
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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