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In Vitro Induction of Mucosa-Type Dendritic Cells by All-Trans Retinoic Acid¹

Institute of Virology and Immunoprophylaxis, Mittelhäusern, Switzerland

Efficient induction of mucosal immunity usually employs nasal or oral vaccination while parenteral immunization generally is ineffective at generating mucosal immune responses. This relates to the unique ability of resident mucosal dendritic cells (DC) to induce IgA switching and to imprint mucosa-specific homing receptors on lymphocytes. Based on the well-established plasticity of the DC system, this study sought to investigate whether peripheral DC could be modulated toward "mucosa-type" DC by treatment with immunomodulatory, and therefore potentially adjuvant-like, factors. In this study, we show that monocyte-derived DCs pretreated with the vitamin A derivative all-trans retinoic acid (RA) indeed acquired several attributes characteristic of mucosal DC: secretion of TGF- and IL-6 and the capacity to augment mucosal homing receptor expression and IgA responses in cocultured lymphocytes. Addition of a TGF--neutralizing Ab to cocultures significantly inhibited ₄₇ integrin, but not CCR9 mRNA expression by the lymphocytes. Both ₄₇ integrin and CCR9 mRNA expression, but not IgA production, were suppressed in the presence of a RA receptor antagonist. None of the observed effects on the lymphocytes were influenced by citral, a retinal dehydrogenase inhibitor, arguing against a role for de novo-synthesized RA. Collectively, our findings identified a novel role for RA as a mucosal immune modulator targeting DC. Our results further demonstrate that DC can act as efficient carriers of RA at least in vitro. Consequently, RA targeting of DC shows potential for promoting vaccine-induced mucosal immune responses via a parenteral route of immunization.

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 the State Secretariat for Education and Research (Grant 03.0519 linked to European Union Project FMD_Improcon Project FP6 503603).

² Address correspondence and reprint requests to Dr. Leslie Saurer, Institute of Virology and Immunoprophylaxis, Sensemattstrasse 293, CH-3147 Mittelhäusern, Switzerland. E-mail address: leslie.saurer{at}ivi.admin.ch

³ Abbreviations used in this paper: MLN, mesenteric lymph node; DC, dendritic cell; RA, retinoic acid; LP, lamina propria; FMDV, foot-and-mouth disease virus; MoDC, monocyte-derived DC; LT, heat-labile enterotoxin; SEB, staphylococcal enterotoxin B; FCM, flow cytometry; MFI, mean fluorescence intensity; RALDH, retinal dehydrogenase; pIC, polyinosine-polycytodolic acid; VitD3, 1,25-dihydroxyvitamin D₃; Ret, retinol.