Immune Reactions against Gene Gun Vaccines Are Differentially Modulated by Distinct Dendritic Cell Subsets in the Skin

Abstract

The skin accommodates multiple dendritic cell (DC) subsets with remarkable functional diversity. Immune reactions are initiated and modulated by the triggering of DC by pathogen-associated or endogenous danger signals. In contrast to these processes, the influence of intrinsic features of protein antigens on the strength and type of immune responses is much less understood. Therefore, we investigated the involvement of distinct DC subsets in immune reactions against two structurally different model antigens, E. coli beta-galactosidase (betaGal) and chicken ovalbumin (OVA) under otherwise identical conditions. After epicutaneous administration of the respective DNA vaccines with a gene gun, wild type mice induced robust immune responses against both antigens. However, ablation of langerin+ DC almost abolished IgG1 and cytotoxic T lymphocytes against betaGal but enhanced T cell and antibody responses against OVA. We identified epidermal Langerhans cells (LC) as the subset responsible for the suppression of anti-OVA reactions and found regulatory T cells critically involved in this process. In contrast, reactions against betaGal were not affected by the selective elimination of LC, indicating that this antigen required a different langerin+ DC subset. The opposing findings obtained with OVA and betaGal vaccines were not due to immune-modulating activities of either the plasmid DNA or the antigen gene products, nor did the differential cellular localization, size or dose of the two proteins account for the opposite effects. Thus, skin-borne protein antigens may be differentially handled by distinct DC subsets, and, in this way, intrinsic features of the antigen can participate in immune modulation.

Neoantigen Expression in Steady-State Langerhans Cells Induces CTL Tolerance

“…We therefore asked, whether these cells also might have acquired a recallable memory phenotype. For that purpose, we subjected TAM-treated LCre-GFPOVA mice to cutaneous gene gun (GG) immunization with a CMV promoter-driven OVA plasmid (pCI-Ova), previously proven to induce robust effector/memory CTL (33, 43). We chose two different time points for the first GG challenge, either at the peak of the primary CTL response (2wks post TAM) or during CTL contraction (4wks post TAM) (see Fig.…”

“…LCs have been implicated in the suppression of immune reactions by activation/expansion of regulatory T (T reg ) cells (18, 21, 43). Interestingly, at the site of GG challenge, we found Foxp3 pos T reg cells substantially increased in the skin of TAM-treated (tolerized) LCre-GFPOVA mice but not in the Cre neg littermates (Fig.…”

“…conditional MHC-II deficiency in LCs increased CHS responses (19). In a recent study, we found that cytotoxic and antibody responses were increased in LC-deficient mice immunized with OVA- but not βGal-encoding GG vaccines, suggesting that antigen-intrinsic features may influence the way they are handled by LCs (43). Notably, some papers demonstrated suppressive effects of LCs on CD4 + or CD8 + T cell responses even in the context of strong maturation signals, suggesting that tolerogenicity could be an inherent feature of LCs that is also efficacious in (or even requires) inflammatory environments (12, 20, 22) These data show that bone marrow chimeras for MHC-II(I-E)-restricted antigen presentation exclusively by LC tolerized adoptively transferred antigen-specific CD4 + T cells, even though mice had been immunized with strong adjuvants (20).…”

A multi-epitope DNA vaccine co-administered with monophosphoryl lipid A adjuvant provides protection against tick transmitted Ehrlichia ruminantium in sheep

“…Permeable molecules are often taken up by Langerhans cells, which then migrate to the draining lymph node followed by differentiation into mature dendritic cells (DC), which will stimulate neighbouring T lymphocytes [32]. These skin DC and keratinocytes play an important role in activation of immune responses after gene gun immunisation [33,34].…”

Microneedle arrays for vaccine delivery: the possibilities, challenges and use of nanoparticles as a combinatorial approach for enhanced vaccine immunogenicity

“…As such, physical and chemical techniques to disrupt the SC barrier have been proposed to enhance antigen delivery through the epidermis for targeting of APCs. The most common physical techniques include tape-stripping, gene guns, iontophoresis, sonophoresis, electroporation and MN [2,[54][55][56], while chemical permeation enhancers such as alcohols, sulphoxides, essential oils, fatty acids and urea, among others, have also been studied in this field [57,58]. While iontophoresis has the advantage of acting more on the drug than on the skin, and consequently lower risk of damages to the skin structure, its use is limited to charged low molecular weight molecules.…”