CD40-Mediated Amplification of Local Immunity by Epithelial Cells Is Impaired by HPV

Tummers, Bart; Goedemans, Renske; Jha, Veena; Meyers, Craig; Melief, Cornelis J.M.; Burg, Sjoerd H. van der; Boer, Judith M.

doi:10.1038/jid.2014.262

Cited by 16 publications

(22 citation statements)

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“…Indeed, hrHPV utilizes its viral proteins and exploits cellular proteins to interfere with signaling of innate immune pathways, potentially postponing the activation of an adaptive immune response (3). HPV may attenuate immune signaling at different levels in the STAT (4–7), IRF, and NFκB pathways (8–14), and has also been shown to impair IFNγ and TNFα signaling (15). Nevertheless, T cells will become activated and migrate to infected sites.…”

Section: Introductionmentioning

confidence: 99%

Human Papillomavirus Downregulates the Expression of IFITM1 and RIPK3 to Escape from IFNγ- and TNFα-Mediated Antiproliferative Effects and Necroptosis

Tummers

Esch

et al. 2016

Front. Immunol.

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The clearance of a high-risk human papillomavirus (hrHPV) infection takes time and requires the local presence of a strong type 1 cytokine T cell response, suggesting that hrHPV has evolved mechanisms to resist this immune attack. Using an unique system for non, newly, and persistent hrHPV infection, we show that hrHPV infection renders keratinocytes (KCs) resistant to the antiproliferative- and necroptosis-inducing effects of IFNγ and TNFα. HrHPV-impaired necroptosis was associated with the upregulation of several methyltransferases, including EZH2, and the downregulation of RIPK3 expression. Restoration of RIPK3 expression using the global histone methyltransferase inhibitor 3-deazaneplanocin increased necroptosis in hrHPV-positive KCs. Simultaneously, hrHPV effectively inhibited IFNγ/TNFα-mediated arrest of cell growth at the S-phase by downregulating IFITM1 already at 48 h after hrHPV infection, followed by an impaired increase in the expression of the antiproliferative gene RARRES1 and a decrease of the proliferative gene PCNA. Knockdown of IFITM1 in uninfected KCs confirmed its role on RARRES1 and its antiproliferative effects. Thus, our study reveals how hrHPV deregulates two pathways involved in cell death and growth regulation to withstand immune-mediated control of hrHPV-infected cells.

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Section: Introductionmentioning

confidence: 99%

Human Papillomavirus Downregulates the Expression of IFITM1 and RIPK3 to Escape from IFNγ- and TNFα-Mediated Antiproliferative Effects and Necroptosis

Tummers

Esch

et al. 2016

Front. Immunol.

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“…The authors concluded that the combined signals are adequate to induce large changes in chemokine secretion, despite lower levels overall. Tummers et al (94) made similar observations by using genome-wide expression analysis of IFN-␥-prestimulated, CD40-ligated primary epithelial cells from foreskin, vagina, and cervix tissues. CD40 ligation produced defined networks of gene expression coordinated by early high expression of IL-8 and TNF.…”

Section: Kc Communicate With Professional Immune Cellsmentioning

confidence: 72%

“…However, CD40 ligation did increase their expression further in HPV-positive cells than in uninfected epithelial cells (94), indicating that CD40 ligation is able to partially reverse gene expression deficits caused by HPV. Similarly, lower levels of CXCL8, CXCL9, CXCL10, and RANTES (measured by ELISA) were secreted by HPV-positive rather than uninfected epithelial cells in response to IFN-␥ stimulation and CD40 ligation, and only supernatants of uninfected epithelial cells were able to increase peripheral blood mononuclear cell migration in response to IFN-␥ stimulation and CD40 ligation (94). The in vivo balance of these immune response-promoting and evasive mechanisms in epithelial cells may significantly impact HPV persistence and disease progression.…”

Section: Kc Communicate With Professional Immune Cellsmentioning

confidence: 90%

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Early Defensive Mechanisms against Human Papillomavirus Infection

Moerman-Herzog

Nakagawa

2015

Clin Vaccine Immunol

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Cervical cancer is the fourth most common cancer in women and is almost exclusively caused by human papillomavirus (HPV) infection. HPV is also frequently associated with other cancers arising from mucosal epithelium, including anal and oropharyngeal cancers, which are becoming more common in both men and women. Viral persistence and progression through precancerous lesion stages are prerequisites for HPV-associated cancer and reflect the inability of cell-mediated immune mechanisms to clear infections and eliminate abnormal cells in some individuals. Cell-mediated immune responses are initiated by innate pathogen sensing and subsequent secretion of soluble immune mediators and amplified by the recruitment and activation of effector T lymphocytes. This review discusses early defensive mechanisms of innate responders to natural HPV infection, their influence on response polarization, and the underappreciated role of keratinocytes in this process. Human papillomavirus (HPV) infects epithelial cells of the skin and mucosal tissues and is best known for its causal role in cervical cancer (1, 2), the fourth most common cancer in women worldwide (3). HPV remains a serious public health problem despite the availability of effective prophylactic vaccines such as Gardasil (Merck, Whitehouse Station, NJ, USA) and Cervarix (GlaxoSmithKline Biologicals, Rixensart, Belgium). In the United States in 2009, cervical cancer represented 53.4% of the newly diagnosed HPV-associated cancers in women and oropharyngeal cancer represented 78.2% of the newly diagnosed HPV-associated cancers in men (4). The incidence rates of HPV-associated anal and oropharyngeal cancers in both men and women increased between 2000 and 2009 (4). In addition, adoption of prophylactic vaccines has been slow. Therefore, understanding of early events that occur upon HPV infection would be important in developing additional modalities for preventing HPV-associated malignancies. This review presents recent advances in our knowledge of the impact of epithelial danger sensing and cytokine responses on the clearance of HPV infections and the emerging role of keratinocytes (KC) as initiators of and partners in the amplification of anti-HPV immunity. HPV INFECTION AND DISEASE PROGRESSIONThe site of infection matters. HPV can be divided into cutaneous and mucosal types based on their tropism for the epithelium of different tissues (5). Mucosal HPV types are further divided into low-and high-risk categories, depending on oncogenicity. Highrisk HPV types cause virtually all cases of cervical cancer (1, 2) and are commonly associated with cancer and high-grade precursor lesions in other mucosal tissues (5-7). HPV16 and -18 cause approximately 70% of cervical cancers, while low-risk HPV6 and -11 cause 90% of anogenital warts. Although HPV broadly infects proliferative cells of cutaneous and mucosal epithelia (2), the risk of HPV-associated disease progression is much higher in the metaplastic transformation zones of the cervix, anus, and oropharynx (8). Active metaplasi...

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“…By contrast, IFNγ, a critical Th1 cytokine, is downregulated in infected women 213 . HPV can manipulate the quality of these infiltrates, preventing the development of effective immune responses 214 .…”

Section: Immune Interactionsmentioning

confidence: 99%

The Interaction Between Human Papillomaviruses and the Stromal Microenvironment

Woodby

Scott

Bodily

2016

Progress in Molecular Biology and Translational Science

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Human papillomaviruses (HPV) are small, double-stranded DNA viruses that replicate in stratified squamous epithelia and cause a variety of malignancies. Current efforts in HPV biology are focused on understanding the virus-host interactions that enable HPV to persist for years or decades in the tissue. The importance of interactions between tumor cells and the stromal microenvironment has become increasingly apparent in recent years, but how stromal interactions impact the normal, benign life cycle of HPVs or progression of lesions to cancer is less understood. Furthermore, how productively replicating HPV impacts cells in the stromal environment is also unclear. Here we bring together some of the relevant literature on keratinocyte-stromal interactions and their impacts on HPV biology. We discuss how HPV oncogenes in infected cells manipulate other cells in their environment, and, conversely, how neighboring cells may impact the efficiency or course of HPV infection.

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CD40-Mediated Amplification of Local Immunity by Epithelial Cells Is Impaired by HPV

Cited by 16 publications

References 54 publications

Human Papillomavirus Downregulates the Expression of IFITM1 and RIPK3 to Escape from IFNγ- and TNFα-Mediated Antiproliferative Effects and Necroptosis

Human Papillomavirus Downregulates the Expression of IFITM1 and RIPK3 to Escape from IFNγ- and TNFα-Mediated Antiproliferative Effects and Necroptosis

Early Defensive Mechanisms against Human Papillomavirus Infection

The Interaction Between Human Papillomaviruses and the Stromal Microenvironment

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