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The Adjuvanticity of a Mannosylated Antigen Reveals TLR4 Functionality Essential for Subset Specialization and Functional Maturation of Mouse Dendritic Cells¹

Kuo-Ching Sheng^*, Martha Kalkanidis, Dodie S. Pouniotis^*, Mark D. Wright, Geoffrey A. Pietersz^2, and Vasso Apostolopoulos^2,3,*

^* Immunology and Vaccine Laboratory, Burnet Institute, Melbourne, Australia; Bio-Organic and Medicinal Chemistry Laboratory, Burnet Institute, Melbourne, Australia and Department of Immunology, Monash University, Australia

The evidence that dendritic cell (DC) subsets produce differential cytokines in response to specific TLR stimulation is robust. However, the role of TLR stimulation in Ag presentation and phenotypic maturation among DC subsets is not clear. Through the adjuvanticity of a novel mannosylated Ag, mannosylated dendrimer OVA (MDO), as a pathogen-associated molecular pattern Ag, we characterized the functionality of GM-CSF/IL-4-cultured bone marrow DC and Flt3 ligand (Flt3-L) DC subsets by Ag presentation and maturation assays. It was demonstrated that both bone marrow DCs and Flt3-L DCs bound, processed, and presented MDO effectively. However, while Flt3-L CD24^high (conventional CD8⁺ equivalent) and CD11b^high (CD8^– equivalent) DCs were adept at MDO processing by MHC class I and II pathways, respectively, CD45RA⁺ plasmacytoid DCs presented MDO poorly to T cells. Successful MDO presentation was largely dependent on competent TLR4 for Ag localization and morphological/phenotypic maturation of DC subsets, despite the indirect interaction of MDO with TLR4. Furthermore, Toll/IL-1 receptor-domain-containing adaptor-inducing IFN-β, but not MyD88, as a TLR4 signaling modulator was indispensable for MDO-induced DC maturation and Ag presentation. Taken together, our findings suggest that DC subsets differentially respond to a pathogen-associated molecular pattern-associated Ag depending on the intrinsic programming and TLRs expressed. Optimal functionality of DC subsets in Ag presentation necessitates concomitant TLR signaling critical for efficient Ag localization and processing.

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

¹ This work was supported a National Health and Medical Research Council project grants (266818 to G.A.P.) (Medical Bioinformatics Genomics and Proteomics Program grant to M.D.W. (406660)) and an American Institute for Cancer Research grant (to M.D.W.). V.A. was a National Health and Medical Research Council R. Douglas Wright Fellow (223316).

² G.A.P. and V.A. contributed equally to this paper.

³ Address correspondence and reprint requests to Dr. Vasso Apostolopoulos, Burnet Institute (Austin Campus), Kronheimer Building, Studley Road, Heidelberg, 3084, Victoria, Australia. E-mail address: vasso{at}burnet.edu.au

⁴ Abbreviations used in this paper: DC, dendritic cell; BM, bone marrow; BMDC, bone marrow dendritic cell; EGCG, (–)-epigallocatechin-3-gallate; E.U., endotoxin unit; Flt3-L, fms-like tyrosine kinase 3 ligand; MD, mannosylated dendrimer; MDO, mannosylated dendrimer OVA; PAMP, pathogen-associated molecular pattern; RT, room temperature; TRIF, Toll/IL-1 receptor-domain-containing adaptor-inducing IFN-β.