Microparticles produced by human papillomavirus type 16 E7-expressing cells impair antigen presenting cell function and the cytotoxic T cell response

J Zhang,M Hibma,M Baird,C Burn,A Braithwaite,M Budhwani,A Tschirley,M Wilson,K Young,K Ly

doi:10.1038/s41598-018-20779-2

Abstract

High-risk, cancer-causing human papillomaviruses (HPV) cause infections of the epidermis that may progress to cancer, including cervical cancer. Viral persistence, contributed to by viral evasion of the host immune response, is associated with the likelihood of cancer developing. Langerhans cells (LCs) are the only professional antigen presenting cells located in the epidermis, therefore may influence the antiviral immune response. Microparticles, or microvesicles, are small membrane particles shed by cells that can exert effects on other cells at both a local and systemic level. We found increased numbers of microparticles were shed from human or mouse keratinocytes expressing the HPV16 E7 oncoprotein, compared with control keratinocytes. Co-culture of LCs with microparticles from E7-expressing cells suppressed the cytotoxic T cell response. We attributed this, at least in part, to the reduction in surface of CD40 and intracellular pro-inflammatory cytokine IL-12 p40 subunit that we measured in the LCs. The evidence provided here shows that co-culture of E7-microparticles with LCs inhibits antigen-specific cytotoxicity. This is an important finding, suggesting that microparticles from HPV-infected cells could suppress the T cell response by regulating LCs, potentially contributing to persistence of HPV infection and cancer.

Highlights

Human papillomavirus type 16 (HPV16) is a cancer-causing virus that can persist, increasing the probability of malignant transformation of cells[1]
In this study we report that expression of HPV16 E7 increased microparticle production from murine and human keratinocytes, and that co-culture of Langerhans cells (LCs) and T cells with those microparticles suppresses antigen-specific cytotoxicity
If these data were to translate to human papillomaviruses (HPV) infection, suppression of the cytotoxic response would likely contribute to evasion of immunity by the HPV infected or transformed cells

Summary

Introduction

Human papillomavirus type 16 (HPV16) is a cancer-causing virus that can persist, increasing the probability of malignant transformation of cells[1]. The reduction in LC density was considered to be at least in part due to virally-mediated suppression of E-cadherin expression on the infected keratinocytes[16]. It is not clear whether those LCs remaining at the site of infection are functionally impaired, and if so the mechanisms by which that might be mediated by the neighbouring infected keratinocytes, as the LCs themselves are not permissive for HPV replication. Cellular microparticles are a heterogeneous group of small membrane fragments, 0.1–1 μm in diameter[17], known as secreted microvesicles or ectosomes They are collectively defined by their size and the surface expression of phosphatidylserine (PS)[18]. Microparticles have been implicated in the transfer of proteins and receptors between cells, cell-to-cell communication, cancers and the modulation of immunity and inflammation[22]

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