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Published online before print March 30, 2006

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(Journal of Leukocyte Biology. 2006;79:1271-1278.)
© 2006 by Society for Leukocyte Biology

Adenoviral-encoded antigens are presented efficiently by a subset of dendritic cells expressing high levels of _vß₃ integrins

Airi Harui^*, Michael D. Roth^*,, Darshni Vira^*, Mihir Sanghvi^*, Hiroyuki Mizuguchi and Saroj K. Basak^*,1

^* Division of Pulmonary & Critical Care Medicine and
Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California Los Angeles; and
National Institute of Biomedical Innovation, Ibaraki, Osaka, Japan

¹Correspondence: Division of Pulmonary & Critical Care, Department of Medicine, UCLA School of Medicine, Los Angeles, CA 90095-1690. E-mail: sbasak{at}mednet.ucla.edu

Dendritic cells (DC) play a central role in antigen presentation and are often targeted by adenoviral (Ad)-based gene therapy. However, DC lack the coxsackie-Ad receptor, and little is known about the process by which they acquire and present Ad-encoded antigens. We examined the expression of ß₃ integrins (CD51/CD61) on mouse bone marrow-derived DC (BM-DC) and their susceptibility to transduction by Ad vectors. Less than 10% of BM-DC precursors expressed CD51, but expression increased over time in culture with granulocyte macrophage-colony stimulating factor (GM-CSF)/interleukin (IL)-4. After 7 days, 28 ± 1.7% of CD11c⁺ DC expressed high levels of CD51 (CD51^hi), and the remaining DC expressed low levels of CD51 (CD51^lo). CD51^hi CD express higher major histocompatibility complex type 1 (MHC I); however, both of the DC subsets expressed similar levels of MHC II and costimulatory molecules. When exposed to a first-generation Ad vector, transgene expression was restricted to the CD51^hi DC subset and blocked by soluble peptides expressing an arginine, glycine, aspartic acid (RGD) sequence, confirming the role of integrins in viral entry. Consistent with this, a modified Ad expressing an RGD-binding sequence in its fiber knob (Ad-RGD) transduced the CD51^hi DC subset with significantly higher efficiency. When BM-DC were transduced with an Ad-expressing ovalbumin (Ad-OVA), the CD51^hi subset proved superior in activating OT-I (T cell receptor-OVA) T cells. Similar to in vitro effects, systemic administration of GM-CSF/IL-4 increased the expression of CD51 on splenic DC and rendered these cells susceptible to Ad transduction. These results suggest that a limited subset of DC expressing high levels of ß₃ integrins is preferentially transduced by Ad vectors and activates CD8⁺ T cell responses against Ad-encoded antigens.

Key Words: gene therapy • vaccination • RGD sequence • ovalbumin • antigen presentation

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