title: Potent induction of antibody-secreting B cells by human dermal-derived CD14+ dendritic cells triggered by dual TLR ligation.
abstract: Targeting CD14(+) dermal-derived dendritic cells (DDCs) is a rational approach for vaccination strategies aimed at improving humoral immune responses, because of their natural ability to stimulate naive B cells. In this study, we show that CD14(+) DDCs express mRNA for TLRs 1-9, but respond differentially to single or paired TLR ligands. Compared to single ligands, some combinations were particularly effective at activating CD14(+) DDCs, as shown by enhanced expression of B cell stimulatory cytokines (IL-6, IL-10, and TNF-α) and more pronounced phenotypic maturation. These combinations were resiquimod (R-848) plus polyinosinic-polycytidylic acid [Poly(I:C)], R-848 plus LPS, Pam3CSK4 plus Poly(I:C), and LPS plus Poly(I:C). We also found that selected TLR ligand pairs [R-848 plus either LPS or Poly(I:C)] were superior to individual agents at boosting the inherent capacity of CD14(+) DDCs to induce naive B cells to proliferate and differentiate into CD27(+) CD38(+) B cells that secrete high levels of IgG and IgA. When treated with the same TLR ligand combinations, CD14(+) DDCs also promoted the differentiation of Th1 (IFN-γ-secreting) CD4(+) T cells, but not of Th2 or Th17 CD4(+) T cells. These observations may help to identify adjuvant strategies aimed at inducing protective immune responses to various pathogens, including but not limited to HIV-1.
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, Cornell University, New York, NY 10021, 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: John P
authors.initials: JP
authors.lastname: Moore
authors.forename: Rogier W
authors.initials: RW
authors.lastname: Sanders
mesh_terms: D000293:Adolescent; D000328:Adult; D000921:Antibody-Producing Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D020405:Dermis / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D008024:Ligands; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis*; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: D016207:Cytokines; D008024:Ligands; D018950:Lipopolysaccharide Receptors; D051193:Toll-Like Receptors