Abstract
Antigen presenting cells (APCs) in skin can promote either antigen-specific effector functions or antigen tolerance, and thus determine clearance or persistence of cutaneous viral infections. Human papillomavirus (HPV) infections can persist in squamous epithelium in immunocompetent individuals, and some persisting HPV infections, particularly with HPV16, promote malignant epithelial transformation. Here, we investigate whether local expression of the HPV16 protein most associated with malignant transformation, HPV16-E7, affects the phenotype and function of APC subsets in the skin. We demonstrate an expanded population of Langerhans cells in HPV16-E7 transgenic skin with distinct cell surface markers which express immune-modulatory enzymes and cytokines not expressed by cells from non transgenic skin. Furthermore, HPV16-E7 transgene expression in keratinocytes attracts new APC subsets to the epidermis. In vivo migration and transport of antigen to the draining lymph node by these APCs is markedly enhanced in HPV16-E7 expressing skin, whereas antigen-processing, as measured by proteolytic cleavage of DQ-OVA and activation of T cells in vivo by APCs, is significantly impaired. These data suggest that local expression of HPV16-E7 in keratinocytes can contribute to persisting infection with this oncogenic virus, by altering the phenotype and function of local APCs.
Highlights
Infection of the anogenital epithelium with an oncogenic human papillomavirus (HPV) initiates 99% of cervical cancers in women
Because HPV clearance is associated with a CD8+ T cell response which is primed by conventional dendritic cells (cDCs), we analysed the phenotype of skin-resident DCs in K14.E7 mice, in which the expression of the non-structural oncoprotein HPV16-E7 as a transgene is driven by the keratinocyte promoter K14 (K14.E7) in murine skin and leads to hyperplasia in the epidermis [17]
To examine presentation of pathogen-derived antigen under these circumstances, we used a mouse in which the HPV16 E7 oncoprotein is expressed from a keratin promoter with resultant epithelial hyperplasia (K14.E7 mice)
Summary
Infection of the anogenital epithelium with an oncogenic human papillomavirus (HPV) initiates 99% of cervical cancers in women. Some reside in secondary lymphoid tissues, where they receive antigens and danger signals either via blood or lymph, while others are located in non-lymphoid tissues such as the lung or mucosal surfaces, where they are directly exposed to pathogens These latter cDCs can migrate to tissue-draining lymph nodes, and either transfer antigens to lymph noderesident cDCs or themselves initiate T cell responses. Because HPV clearance is associated with a CD8+ T cell response which is primed by cDCs, we analysed the phenotype of skin-resident DCs in K14.E7 mice, in which the expression of the non-structural oncoprotein HPV16-E7 as a transgene is driven by the keratinocyte promoter K14 (K14.E7) in murine skin and leads to hyperplasia in the epidermis [17]. Within the K14.E7 skin specific immunological microenvironment, skin-resident K14.E7 DCs have impaired ability to process antigen and prime CD8+ antigen-specific T cells, suggesting that the immune-suppressive HPV-E7-expressing skin effects DC functionality
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