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Myeloid and Plasmacytoid Dendritic Cells Are Susceptible to Recombinant Adenovirus Vectors and Stimulate Polyfunctional Memory T Cell Responses

Karin Loré^1,2,*,, William C. Adams^*,, Menzo Havenga, Melissa L. Precopio^*, Lennart Holterman, Jaap Goudsmit and Richard A. Koup^*

^* Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; and Crucell Holland BV, Leiden, The Netherlands

Although replication-incompetent recombinant adenovirus (rAd) type 5 is a potent vaccine vector for stimulating T and B cell responses, high seroprevalence of adenovirus type 5 (Ad5) within human populations may limit its clinical utility. Therefore, alternative adenovirus serotypes have been studied as vaccine vectors. In this study, we characterized the ability of rAd5 and rAd35 to infect and induce maturation of human CD11c⁺ myeloid dendritic cells (MDCs) and CD123⁺ plasmacytoid dendritic cells (PDCs), and their ability to stimulate Ag-specific T cells. Both MDCs and PDCs were found to express the primary receptor for Ad35 (CD46) but not Ad5 (coxsackie-adenovirus receptor; CAR). Both dendritic cell (DC) subsets were also more susceptible to rAd35 than to rAd5. MDCs were more susceptible to both rAd35 and rAd5 than were PDCs. Whereas rAd35 used CD46 for entry into DCs, entry of rAd5 may be through a CAR-independent pathway. Exposure to rAd35 but not rAd5 induced high levels of IFN- in PDCs and phenotypic differentiation in both DC subsets. MDCs and PDCs exposed to either rAd5 or rAd35 encoding for CMV pp65 were able to present pp65 and activate CMV-specific memory CD8⁺ and CD4⁺ T cells in a dose-dependent manner, but MDCs stimulated the highest frequencies of pp65-specific T cells. Responding T cells expressed multiple functions including degranulation (CD107a surface mobilization) and production of IFN-, IL-2, TNF-, and MIP-1. Thus, the ability of rAd35 to naturally target important DC subsets, induce their maturation, and appropriately present Ag to T cells may herald greater in vivo immunogenicity than has been observed with rAd5.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ K.L. was the recipient of a grant from the Swedish Society of Medical Research.

² Address correspondence and reprint requests to Dr. Karin Loré, Center for Infectious Medicine, Karolinska Institutet, F59, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden. E-mail address: karin.lore{at}ki.se

³ Abbreviations used in this paper: DC, dendritic cell; MDC, myeloid DC; PDC, plasmacytoid DC; rAd, recombinant adenovirus vector; ip, infectious particle; CAR, coxsackie-adenovirus receptor; CHO, Chinese hamster ovary; BCL, B cell line.