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.