Intradermally administered TLR4 agonist GLA-SE enhances the capacity of human skin DCs to activate T cells and promotes emigration of Langerhans cells

The natural TLR4 agonist lipopolysaccharide (LPS) has notable adjuvant activity. However, it is not useful as a vaccine adjuvant due to its toxicity. Glucopyranosyl lipid A (GLA) is a synthetic derivative of the lipid A tail of LPS with limited cytotoxicity, but strong potential to induce immune responses in mice, guinea pigs, non-human primates, and humans. In this study we determined how this synthetic TLR4 agonist affects the function of different subsets of human skin dendritic cells (DCs). The effect of GLA in an aqueous formulation (GLA-AF) or in an oil-in-water emulsion (GLA-SE) was compared to that of LPS and TLR3 agonist poly(I:C) using a human skin explant model with intradermal injections for the administration of the agonists. Intradermal injection of GLA-SE or LPS, but not GLA-AF, enhanced the emigration of CD1ahigh/langerin+ Langerhans cells (LCs), but not dermal DCs (DDCs). LCs and CD14− DDCs exhibited an enhanced mature phenotype following intradermal administration of either of the two GLA formulations tested, similar to DCs that emigrated from LPS-injected skin. However, only injection of GLA-SE resulted in a significant increase in the production of the wide range of cytokines that is observed with LPS. Moreover, DCs that emigrated from GLA-SE-injected skin induced stronger CD4+ T-cell activation, as indicated by a more pronounced T-cell proliferation, than DCs from skin injected with GLA-AF or LPS. Altogether, our data show that GLA-SE has a notable potency to stimulate the function of skin DCs, indicating that GLA-SE may be a good candidate as adjuvant for vaccines administered via the intradermal route.

► Synthetic TLR4-agonist GLA has differential effects on DC subsets in a human skin explant model.
► Intradermal injection of GLA in a stable oil-in-water emulsion enhances Langerhans cell migration.
► DCs from GLA-injected skin are more mature and induce stronger T-cell activation.
► GLA-injected skin produces significantly more pro-inflammatory cytokines.
► GLA formulations may be suitable adjuvants for intradermally administered vaccines.