title: Clinical adjuvant combinations stimulate potent B-cell responses in vitro by activating dermal dendritic cells.
abstract: CD14(+) dermal DCs (CD14(+) DDCs) have a natural capacity to activate naïve B-cells. Targeting CD14(+) DDCs is therefore a rational approach for vaccination strategies aimed at improving humoral responses towards poorly immunogenic antigens, for example, HIV-1 envelope glycoproteins (Env). Here, we show that two clinically relevant TLR ligand combinations, Hiltonol plus Resiquimod and Glucopyranosyl lipid A plus Resiquimod, potently activate CD14(+) DDCs, as shown by enhanced expression of multiple cytokines (IL-6, IL-10, IL-12p40 and TNF-α). Furthermore, the responses of CD14(+) DDCs to these TLR ligands were not compromised by the presence of HIV-1 gp120, which can drive immunosuppressive effects in vitro and in vivo. The above TLR ligand pairs were better than the individual agents at boosting the inherent capacity of CD14(+) DDCs to induce naïve B-cells to proliferate and differentiate into CD27(+) CD38(+) B-cells that secrete high levels of immunoglobulins. CD14(+) DDCs stimulated by these TLR ligand combinations also promoted the differentiation of Th1 (IFN-γ-secreting), but not Th17, CD4(+) T-cells. These observations may help to identify adjuvant strategies aimed at inducing better antibody responses to vaccine antigens, including, but not limited to HIV-1 Env.
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Katie
authors.initials: K
authors.lastname: Matthews
authors.forename: Nancy P Y
authors.initials: NP
authors.lastname: Chung
authors.forename: Per Johan
authors.initials: PJ
authors.lastname: Klasse
authors.forename: Magda
authors.initials: M
authors.lastname: Moutaftsi
authors.forename: Darrick
authors.initials: D
authors.lastname: Carter
authors.forename: André M
authors.initials: AM
authors.lastname: Salazar
authors.forename: Steven G
authors.initials: SG
authors.lastname: Reed
authors.forename: Rogier W
authors.initials: RW
authors.lastname: Sanders
authors.forename: John P
authors.initials: JP
authors.lastname: Moore
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000328:Adult; D000368:Aged; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D002266:Carboxymethylcellulose Sodium / Q000031:analogs & derivatives* / Q000494:pharmacology; D016764:Cell Polarity; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D004357:Drug Synergism; D015699:HIV Envelope Protein gp120 / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007801:Langerhans Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008050:Lipid A / Q000031:analogs & derivatives* / Q000494:pharmacology; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008213:Lymphocyte Activation; D008875:Middle Aged; D011070:Poly I-C / Q000494:pharmacology*; D011107:Polylysine / Q000031:analogs & derivatives* / Q000494:pharmacology; D012867:Skin; D051193:Toll-Like Receptors / Q000819:agonists; D014611:Vaccination; D055815:Young Adult
chemical_list: D000276:Adjuvants, Immunologic; D016207:Cytokines; D015699:HIV Envelope Protein gp120; D007093:Imidazoles; D008050:Lipid A; D018950:Lipopolysaccharide Receptors; D051193:Toll-Like Receptors; C514793:gp120 protein, Human immunodeficiency virus 1; D011107:Polylysine; C019531:poly ICLC; D002266:Carboxymethylcellulose Sodium; D011070:Poly I-C; C402365:resiquimod