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* Department of Microbiology and Immunology and
Carolina Vaccine Institute, University of North Carolina, Chapel Hill, NC 27599;
Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520; and
Department of Pathology, and Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710
The strongest mucosal immune responses are induced following mucosal Ag delivery and processing in the mucosal lymphoid tissues, and much is known regarding the immunological parameters which regulate immune induction via this pathway. Recently, experimental systems have been identified in which mucosal immune responses are induced following nonmucosal Ag delivery. One such system, footpad delivery of Venezuelan equine encephalitis virus replicon particles (VRP), led to the local production of IgA Abs directed against both expressed and codelivered Ags at multiple mucosal surfaces in mice. In contrast to the mucosal delivery pathway, little is known regarding the lymphoid structures and immunological components that are responsible for mucosal immune induction following nonmucosal delivery. In this study, we have used footpad delivery of VRP to probe the constituents of this alternative pathway for mucosal immune induction. Following nonmucosal VRP delivery, J chain-containing, polymeric IgA Abs were detected in the peripheral draining lymph node (DLN), at a time before IgA detection at mucosal surfaces. Further analysis of the VRP DLN revealed up-regulated 
4β7 integrin expression on DLN B cells, expression of mucosal addressin cell adhesion molecule 1 on the DLN high endothelia venules, and production of IL-6 and CC chemokines, all characteristics of mucosal lymphoid tissues. Taken together, these results implicate the peripheral DLN as an integral component of an alternative pathway for mucosal immune induction. A further understanding of the critical immunological and viral components of this pathway may significantly improve both our knowledge of viral-induced immunity and the efficacy of viral-based vaccines.
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 grants from the National Institutes of Allergy and Infectious Diseases/National Institutes of Health: P01-AI046023 (to R.E.J.), R01-AI051990 (to R.E.J.), U01-AI070976 (to R.E.J.), and T32-AI007419 (to J.M.T.).
2 Current address: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520.
3 Current address: Precision BioSciences, Durham, NC 27709.
4 Address correspondence and reprint requests to Dr. Robert E. Johnston, Carolina Vaccine Institute, CB 7292, 9th Floor Burnett Womack, UNC-Chapel Hill, Chapel Hill, NC 27599. E-mail address: robert_johnston{at}med.unc.edu
5 Abbreviations used in this paper: MAdCAM-1, mucosal addressin cell adhesion molecule 1; DC, dendritic cell; DLN, draining lymph node; HA, hemagglutinin; HEV, high endothelial venule; I-Flu, inactivated influenza virus; MLN, mesenteric lymph node; VEE, Venezuelan equine encephalitis virus; VRP, VEE replicon particles; PP, Peyer’s patch; PNAd, peripheral lymph node addressin; IP, immunoprecipitation; IU, infectious unit.
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