Abstract
The skin is an attractive site for vaccination due to its accessibility and presence of immune cells surveilling this barrier. However, knowledge of antigen processing and presentation upon dermal vaccination is sparse. In this study we determined antigen processing routes that lead to CD8+ T cell activation following dermal DNA tattoo immunization, exploiting a model antigen that contains an immunoproteasome-dependent epitope. In agreement with earlier reports, we found that DNA tattoo immunization of wild type (WT) mice triggered vigorous responses to the immunoproteasome-dependent model epitope, whereas gene-deficient mice lacking the immunoproteasome subunits β5i/LMP7 and β2i/MECL1 failed to respond. Unexpectedly, dermal immunization both of irradiated bone marrow (BM) reconstituted mice in which the BM transplant was of WT origin, and of WT mice transplanted with immunoproteasome subunit-deficient BM induced a CD8+ T cell response to the immunoproteasome-dependent epitope, implying that both BM and host-derived cells contributed to processing of delivered model antigen. Depletion of radiation-resistant Langerhans cells (LC) from chimeric mice did not diminish tattoo-immunization induced CD8+ T cell responses in most mice, illustrating that LC were not responsible for antigen processing and CD8+ T cell priming in tattoo-immunized hosts. We conclude that both BM and non-BM-derived cells contribute to processing and cross-presentation of antigens delivered by dermal DNA tattoo immunization.
Highlights
The earliest successful vaccination against smallpox was accomplished by cutaneous vaccination
Using bone marrow (BM) chimeric mice, composed of wild type (WT), CD207-diptheria toxin receptor knock in (KI) – and b2i/MECL1À/Àb5i/LMP7À/À (KO) recipients, reconstituted with WT – or knock out (KO) BM, we show that both BM- and non-BM-derived cells contribute to the processing of professional antigen presenting cells (pAPC)-presented, dermally delivered vaccine antigen, and that radiation-resistant Langerhans cells (LC) are not responsible for the CD8+ T cell activation
To determine which cells process the antigens that prime CD8+ T cell responses following dermal DNA tattoo immunization, a p/ DNA vaccine was constructed encoding the adenovirus-derived E1B192-200 and E1A234-243 epitopes [14] in context of their natural flanking sequences, and preceded by tetanus toxin fragment C domain 1 (TTFC), to enhance the immunogenicity of this construct [15]
Summary
The earliest successful vaccination against smallpox was accomplished by cutaneous vaccination. A number of cutaneous delivery methods are being tested, including different types of microneedles and tattoo immunization. While these methods have been demonstrated to induce both humoral and cellular responses, the underlying mechanisms contributing to cellular immune activation have only partially been explored. Different studies have defined a variety of pAPC subsets as responsible for the interaction with vaccine antigen-specific CD8+ T cells, including dendritic cells (DC) residing in the lymph nodes, langerin+ dermal DC, and Langerhans cells (LC), LC may either have a stimulatory or inhibitory role [1,2,3,4]. While induced CD8+ T cell responses are primed by either of these DC subsets, it remains unclear whether these DC process the epitopes they present, or acquire them from other, non-dendritic, cells
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