Innate Molecular and Cellular Signature in the Skin Preceding Long-Lasting T Cell Responses after Electroporated DNA Vaccination

• Published in: The Journal of immunology (1950) Vol. 9; no. 12; pp. 3375 - 3388
• Main Authors: Adam, Lucille, Tchitchek, Nicolas, Todorova, Biliana, Rosenbaum, Pierre, Joly, Candie, Poux, Candice, Chapon, Catherine, Spetz, Anna-Lena, Ustav, Mart, Le Grand, Roger, Martinon, Frédéric
• Format: Journal Article
• Language: English
• Published: 10.05.2020
• Subjects: Immunology; Life Sciences; dendritic cell EP; gene transport unit; M1; electroporation GTU; M2; skin; GTU; nonhuman primate; phosphate-buffered saline; multidimensional scaling NHP; type 1 macrophages; PRR; type 2 macrophages; type 2 macrophages MDS; NHP; gene transport unit LC; polymorphonuclear leukocytes PRR; TLR; phosphate-buffered saline PMN; MDS; Langerhans cell M1; Toll-like receptor; DNA vaccine; PBS; polymorphonuclear leukocytes; type 1 macrophages M2; EP; Pattern Recognition Receptors TLR; DNA vaccine electroporation AIM-2 innate response skin NHP Innate skin DNA-vaccine reponses antigen presenting cell DC; PMN; NHP Innate skin DNA-vaccine reponses antigen presenting cell; nonhuman primate PBS; Langerhans cell; LC; Pattern Recognition Receptors; electroporation; multidimensional scaling; AIM-2; dendritic cell; innate response; DC
• ISSN: 1550-6606
• DOI: 10.3389/fimmu.2018.00870

Abstract DNA vaccines delivered with electroporation (EP) have shown promising results in preclinical models and are evaluated in clinical trials. In this study, we aim to characterize early mechanisms occurring in the skin after intradermal injection and EP of the auxoGTUmultiSIV DNA vaccine in nonhuman primates. First, we show that EP acts as an adjuvant by enhancing local inflammation, notably via granulocytes, monocytes/macrophages, and CD1aint-expressing cell recruitment. EP also induced Langerhans cell maturation, illustrated by CD86, CD83, and HLA-DR upregulation and their migration out of the epidermis. Second, we demonstrate the crucial role of the DNA vaccine in soluble factors release, such as MCP-1 or IL-15. Transcriptomic analysis showed that EP played a major role in gene expression changes postvaccination. However, the DNA vaccine is required to strongly upregulate several genes involved in inflammatory responses (e.g., Saa4), cell migration (e.g., Ccl3, Ccl5, or Cxcl10), APC activation (e.g., Cd86), and IFN-inducible genes (e.g., Ifit3, Ifit5, Irf7, Isg15, orMx1), illustrating an antiviral response signature. Also, AIM-2, a cytosolic DNA sensor, appeared to be strongly upregulated only in the presence of the DNA vaccine and trends to positively correlate with several IFN-inducible genes, suggesting the potential role of AIM-2 in vaccine sensing and the subsequent innate response activation leading to strong adaptive T cell responses. Overall, these results demonstrate that a combined stimulation of the immune response, in which EP and the auxoGTUmultiSIV vaccine triggered different components of the innate immunity, led to strong and persistent cellular recall responses.