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CD11c^high Dendritic Cells Are Essential for Activation of CD4⁺ T Cells and Generation of Specific Antibodies following Mucosal Immunization¹

Linda Fahlén-Yrlid,^* Tobias Gustafsson,^* Jessica Westlund,^* Anna Holmberg,^* Anna Strömbeck,^* Margareta Blomquist,^* Gordon G. MacPherson, Jan Holmgren,^* and Ulf Yrlid^2*

^*Department of Microbiology and Immunology, Institute of Biomedicine, The Mucosal Immunobiology and Vaccine Center (MIVAC) and University of Gothenburg Vaccine Research Institute (GUVAX), The Sahlgrenska Academy at the University of Gothenburg, Göteborg, Sweden; and Sir William Dunn School of Pathology, Oxford, United Kingdom

To generate vaccines that protect mucosal surfaces, a better understanding of the cells required in vivo for activation of the adaptive immune response following mucosal immunization is required. CD11c^high conventional dendritic cells (cDCs) have been shown to be necessary for activation of naive CD8⁺ T cells in vivo, but the role of cDCs in CD4⁺ T cell activation is still unclear, especially at mucosal surfaces. The activation of naive Ag-specific CD4⁺ T cells and the generation of Abs following mucosal administration of Ag with or without the potent mucosal adjuvant cholera toxin were therefore analyzed in mice depleted of CD11c^high cDCs. Our results show that cDCs are absolutely required for activation of CD4⁺ T cells after oral and nasal immunization. Ag-specific IgG titers in serum, as well as Ag-specific intestinal IgA, were completely abrogated after feeding mice OVA and cholera toxin. However, giving a very high dose of Ag, 30-fold more than required to detect T cell proliferation, to cDC-ablated mice resulted in proliferation of Ag-specific CD4⁺ T cells. This proliferation was not inhibited by additional depletion of plasmacytoid DCs or in cDC-depleted mice whose B cells were MHC-II deficient. This study therefore demonstrates that cDCs are required for successful mucosal immunization, unless a very high dose of Ag is administered.

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 study was supported by grants from the Swedish Research Council, Swedish Foundation for Strategic Research through its support of the Mucosal Immunobiology and Vaccine Center, Marianne and Marcus Wallenberg Foundation, Jeansson Foundation, Åke Wiberg Foundation, Clas Grochinsky Foundation, Magnus Bergvall Foundation and the Royal Arts and Society of Arts and Science in Göteborg.

² Address correspondence and reprint requests to Dr. Ulf Yrlid, Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Box 435, 40530 Göteborg, Sweden. E-mail address: ulf.yrlid{at}microbio.gu.se

³ Abbreviations used in this paper: DC, dendritic cell; DTx, diphtheria toxin; cDC, conventional dendritic cell; DTR, diphtheria toxin receptor; VSV, vesicular stomatatis virus; LN, lymph node; pDC, plasmacytoid dendritic cell; CT, cholera toxin; Tg, transgenic; BM, bone marrow; WT, wild type; 7AAD, 7-aminoactinomycin D; CTB, cholera toxin subunit B; MLN, mesenteric LN; PP, Peyer’s patches.