Antigen-presenting cells can capture antigens that are deposited in the skin, including vaccines given subcutaneously. These include different dendritic cells (DC) such as epidermal Langerhans cells (LC), dermal DC and dermal langerin+ DC.
To evaluate access of dermal antigens to skin DC, we used mAb to two C-type lectin endocytic receptors, DEC-205/CD205 and langerin/CD207. When applied to murine and human skin explant cultures, these mAb were efficiently taken up by epidermal LC. Additionally, anti-DEC-205 targeted langerin+ CD103+ and langerin− CD103− mouse dermal DC. Unexpectedly, intradermal injection of either mAb, but not isotype control, resulted in strong and rapid labelling of LC in situ, implying that large molecules can diffuse through the basement membrane into the epidermis. Epidermal LC targeted in vivo by ovalbumin-coupled anti-DEC-205 potently presented antigen to CD4+ and CD8+ T cells. Thus, epidermal LC play a major role in uptake of lectin-binding ligands under standard vaccination conditions.
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Incorporation of antigens by dendritic cells (DCs) increases when antigens are targeted to endocytic receptors by monoclonal antibodies (mAb). We have previously demonstrated in the mouse that mAb against C-type lectins administered intradermally are taken up by epidermal Langerhans cells (LCs), dermal Langerinneg DCs and dermal Langerin+ DCs in situ. However, the relative contribution of these skin DC subsets to the induction of immune responses after antigen targeting has not been addressed in vivo.
We show here that murine epidermal LCs and dermal DCs transport intradermally injected mAb against the lectin receptor DEC-205/CD205 in vivo. Skin DCs targeted in situ with mAb migrated through lymphatic vessels in steady state and inflammation. In the skin-draining lymph nodes, targeting mAb were found in resident CD8α+ DCs and in migrating skin DCs. More than 70% of targeted DCs expressed Langerin, including dermal Langerin+ DCs and LCs. Numbers of targeted skin DCs in the nodes increased 2-3-fold when skin was topically inflamed by the TLR7 agonist imiquimod.
Complete removal of the site where ovalbumin-coupled anti-DEC-205 had been injected decreased endogenous cytotoxic responses against ovalbumin peptide-loaded target cells by 40-50%. Surprisingly, selective ablation of all Langerin+ skin DCs in Langerin-Diphtheria-Toxin-Receptor knock-in mice did not affect such responses, independent of the adjuvant chosen. Thus, in cutaneous immunization strategies where antigen is targeted to DCs, Langerin+ skin DCs play a major role in transport of anti-DEC-205 mAb, although Langerinneg dermal DCs and CD8α+ DCs are sufficient to subsequent CD8+ T cell responses.
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