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A Human Dendritic Cell Subset Receptive to the Venezuelan Equine Encephalitis Virus-Derived Replicon Particle Constitutively Expresses IL-32¹

Kevin P. Nishimoto^*,, Amanda K. Laust^*, and Edward L. Nelson^2,*,,

^* Molecular Biology and Biochemistry, School of Biological Sciences, Department of Medicine, Division of Hematology/Oncology, School of Medicine, and Center for Immunology, University of California at Irvine, Irvine, CA 92697

Dendritic cells (DCs) are a diverse population with the capacity to respond to a variety of pathogens. Because of their critical role in pathogenesis and Ag-specific adaptive immune responses, DCs are the focus of extensive study and incorporation into a variety of immunotherapeutic strategies. The diversity of DC subsets imposes a substantial challenge to the successful development of DC-based therapies, requiring identification of the involved subset(s) and the potential roles each contributes to the immunologic responses. The recently developed and promising Venezuelan equine encephalitis replicon particle (VRP) vector system has conserved tropism for a subset of myeloid DCs. This immunotherapeutic vector permits in situ targeting of DCs; however, it targets a restricted subset of DCs, which are heretofore uncharacterized. Using a novel technique, we isolated VRP-receptive and -nonreceptive populations from human monocyte-derived DCs. Comparative gene expression analysis revealed significant differential gene expression, supporting the existence of two distinct DC populations. Further analysis identified constitutive expression of the proinflammatory cytokine IL-32 as a distinguishing characteristic of VRP-receptive DCs. IL-32 transcript was exclusively expressed (>50 fold) in the VRP-receptive DC population relative to the background level of expression in the nonreceptive population. The presence of IL-32 transcript was accompanied by protein expression. These data are the first to identify a subset of immature monocyte-derived DCs constitutively expressing IL-32 and they provide insights into both DC biology and potential mechanisms employed by this potent vector system.

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 This work was supported by Pacific Southwest Regional Center of Excellence in Biodefense and Emerging Infectious Disease Research.

² Address correspondence and reprint requests to Dr. Edward L. Nelson, University of California at Irvine, Hewitt Hall, Irvine, CA 92697. E-mail address: enelson{at}uci.edu

³ Abbreviations used in this paper: DC, dendritic cell; bVRP, biotinylated VRP; MOI, multiplicity of infection; EGFP, enhanced green fluorescent reporter protein; NK4, NK transcript 4; PPDE, posterior probability of differential expression; VEE, Venezuelan equine encephalitis; VRP, VEE replicon particle.