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.
Highlights
Dendritic cells (DC) in the skin comprise at least five subpopulations with different ontogenies and phenotypes [1,2,3,4]
In previous studies we found that langerin+ dermal DC (LdDC) but not epidermal Langerhans cells (LC) were required for cytotoxic T lymphocytes (CTL) and IgG1 antibodies against beta-galactosidase after gene gun (GG) vaccination [18, 19]
In a previous study we found that the absence of langerin+ DC resulted in a strong reduction of CD8+ T cell responses to a βGal gene gun vaccine [18]
Summary
Dendritic cells (DC) in the skin comprise at least five subpopulations with different ontogenies and phenotypes [1,2,3,4]. The dermis accommodates two langerinneg DC subsets that are positive or negative for CD11b, respectively [8]. In face of this complexity it was for a long time difficult to dissect the roles of individual DC subsets in vivo. Transgenic mouse models for constitutive or inducible LC deficiency [9, 10], or diphtheria toxin (DT)-mediated ablation of all langerin+ subsets [11, 12] have greatly assisted in the investigation of skin DC functions in vivo. Distinct DC subsets displayed a clear functional specialization, with differential roles in CTL activation, Th cell polarization, antigen cross presentation, the induction of tolerance, or the maintenance of homeostasis in the commensal skin flora [8, 14,15,16,17]
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